Nuclear organization and 3D chromatin architecture in cognition and neuropsychiatric disorders
© The Author(s). 2016
Received: 30 May 2016
Accepted: 6 August 2016
Published: 5 September 2016
The current view of neuroplasticity depicts the changes in the strength and number of synaptic connections as the main physical substrate for behavioral adaptation to new experiences in a changing environment. Although transcriptional regulation is known to play a role in these synaptic changes, the specific contribution of activity-induced changes to both the structure of the nucleus and the organization of the genome remains insufficiently characterized. Increasing evidence indicates that plasticity-related genes may work in coordination and share architectural and transcriptional machinery within discrete genomic foci. Here we review the molecular and cellular mechanisms through which neuronal nuclei structurally adapt to stimuli and discuss how the perturbation of these mechanisms can trigger behavioral malfunction.
KeywordsNuclear structure Chromatin Epigenetics Neuronal plasticity Chromosomal interactions Neuropsychiatric disorders
In the search for mechanisms that underlie behavioral plasticity, functional and structural changes at synapses are at the core of the theoretical framework. Processes such as long-term potentiation (LTP) or synaptogenesis are thought to be crucial for the adaptation of neuronal circuits to changing environmental conditions . Both stimulus-driven transcriptional responses  and different forms of epigenetic regulation  are known to participate in these processes. However, only recently high-order chromatin architecture has been implicated in the neurobiology of behavior . Cell biology studies have revealed that the compartmentalization of chromatin dictates the location of specific genes within the neuronal nucleus, thereby conditioning the mechanisms controlling their transcription . The complexity and cellular heterogeneity of neuronal tissue make technically difficult the investigation of the contribution of activity-induced changes in chromatin architecture to neuronal plasticity. However, as technological advances enable deeper insight into the genomic landscape of neurons, increasing evidence indicates that individual genes do not work in isolation; instead, they share niches and machinery within the cell nucleus that sustain coordinated regulation. The levels of regulation include changes in nuclear geometry and subnuclear structures, dynamic interactions of structural proteins and the transcription machinery with chromatin, the relocation of genes into transcriptionally active or repressive areas, and chromatin loopings that activate regulatory sequences. In the following sections, we review recent studies that have begun to unveil the contribution of these novel mechanisms to neuronal plasticity, and highlight how their malfunction can contribute to the on-set or further development of neuropsychiatric disorders.
Neuronal nuclear structure and its regulation by neuronal activity
In eukaryotic nuclei, DNA is wrapped around an octameric histone core comprising of two copies of each of the canonical histones H2A, H2B, H3 and H4. This basic structure, known as a nucleosome, is repeated along the double-stranded DNA, with a fifth type of histone (the linker histone H1) bridging together consecutive nucleosomes. In this fashion, long DNA strands condense with architectural proteins to form chromatin. Based on the level of compaction we can distinguish three main forms of chromatin. These forms differ biochemically with respect to the presence of specific post-translational modifications (PTMs) at the histone tails and to the binding of structural proteins. Euchromatin, a transcriptionally active form is characterized by permissive marks such as the trimethylation of histone 3 at lysine 4 (H3K4me3), and the acetylation of different lysine residues at the histone tails. In contrast, heterochromatin is a transcriptionally silent form, and is decorated by repressive epigenetic marks. It can be found in two different functional states: constitutive heterochromatin that is characterized by DNA methylation at CpGs and histone H3 trimethylation at lysine 9 (H3K9me3), and facultative heterochromatin, which, as suggested by its name, can harbor transcriptional activity and is marked by H3K27me3 .
Apart from chromocenters and peripheral heterochromatin, the interphasic neuronal nucleus is structurally complex  (Fig. 1b). Based on conventional microscopy techniques, we can define three major components: the nuclear lamina and associated heterochromatin, the nucleoplasm that is defined by a fine and relatively homogeneous granular matrix, and the different internal macrostructures that disrupt this granular matrix. In the following sections we will discuss each of these components and their responses to neuronal activation.
Nuclear envelope and lamina
Nuclear architecture and genome organization depend on the integrity of the nuclear envelope, a boundary that separates the cytoplasm from the nucleoplasmic reticulum. This boundary is composed of two phospholipid bilayers spanned at intervals by proteins that act as nuclear pores. The nuclear envelope is not an inert barrier, it participates in different processes including gene regulation and the transport of ions and macromolecular cargos . Its geometry in neurons is rather plastic and responds to neuronal activity . In the case of hippocampal neurons, there are both spherical and highly infolded nuclei featuring different degrees of complexity, with nuclear infoldings being antagonistically regulated by synaptic and extrasynaptic NMDA receptors . Infolded nuclei typically have larger surfaces accompanied by an increase in nuclear pore complexes (NPC) that facilitates calcium influx and the transport between the nuclear and cytosolic plasmas.
Internally attached to the nuclear envelope is the nuclear lamina, whose main components are the lamin proteins A/C, B1 and B2 . These proteins form a scaffold and bind to peripheral chromatin, playing an essential role in transcriptional regulation. Cellular biology studies have shown that the lamin composition of the nuclear envelope changes throughout neuronal differentiation. While primary progenitors have lamin A/C, B1 and B2 in equal amounts, neuroblasts have more B1 and some B2, and mature neurons preferentially express B2, some A/C, and little B1 . Genetic experiments in mice have demonstrated that lamins B1 and B2, despite their great sequence homology, have unique roles in the developing brain, and that increased production of one does not compensate for the loss of the other [19, 20].
Lamin-associated chromatin domains (LADs) are enriched in transcriptional and epigenetic repressors . Although the attachment of chromatin to the nuclear lamina has been found to promote transcriptional repression , this relationship is not strict. In fact, genes in both the margin and the center can be expressed, although peripheral genes are less likely to be transcribed than inactive genes dissociated from the lamina [22, 23]. Although little is still known about signal transduction across the nuclear envelope in neurons, a recent study on the role of the calcium signaling modulator Sigma-1 receptor (Sig-1R) demonstrated that the translocation of this receptor from the endoplasmic reticulum into the nuclear envelope upon cocaine administration may contribute to the addictive properties of this drug. Once in the nucleus, Sig-1R recruits chromatin-remodeling molecules such as lamin A/C, barrier-to-autointegration factor (BAF) and histone deacetylases (HDAC) to specific loci, shutting down the expression of monoamine oxidase B (MAOB), an enzyme that is dramatically upregulated during withdrawal and whose inhibition may contribute to the reinforcing properties of cocaine .
Nuclear bodies are subnuclear divisions that lack a membrane. In addition to the afore discussed chromocenters, which are the most prominent type of nuclear body in mature neurons, one can also typically find (i) a single nucleolus where rRNA transcription takes place, (ii) the Cajal bodies (CBs) that are adjacent to the nucleolus and are the site for small nuclear ribonucleic protein (snRNP) assembly, (iii) nuclear speckles that are highly enriched in splicing factors, and (iv) promyelocytic leukemia (PML) bodies that hold unknown functions  (Fig. 1b). As discussed for the nuclear lamina, these structures can undergo dramatic changes upon neuronal activation. For example, the amyloid precursor protein, intracellular domain–associated protein-1 (AIDA-1d) is a post-synaptically localized protein that translocates into the nucleus after synaptic stimulation. This translocation increases the number of nucleoli and may eventually promote protein synthesis . Notably, nucleolar integrity has been shown to be necessary for LTP . PML bodies are also sensitive to changes in activity; they tend to cluster into fewer, but denser and larger foci as a result of epileptic activity or exposure to behaviorally stressful conditions such as restraint . In turn, the disruption of CBs and splicing speckles has been also associated with pathological states [29, 30], but the molecular machinery underlying these changes and its contribution to pathoetiology remains unknown.
The nucleoplasm is not an inert and homogeneous matrix filled with euchromatin fibers as once thought. Static electron microscopy images have since been challenged by the dynamic scenario revealed by molecular studies that explore short and long-range interactions between DNA sequences that are located thousands of bases apart or even in different chromosomes . The use of super-resolution microscopy has recently allowed the direct visualization of fibers rich in nucleosomes, which can be frequently grouped into “clutches” and are interspaced with nucleosome-depleted DNA. The density of these clutches differs across cell types with stem cells having a lower density compared to mature neurons .
Fine submegabase 3D interactions are essential for neuronal commitment and are also likely to contribute to the regulation of gene expression during neuronal plasticity processes. We will discuss in the next section the novel techniques available and the seminal studies investigating how neuronal activation causes changes in the fine structure of the nucleoplasm.
Neuronal 3D genome organization and its regulation by neuronal activity
Given their small scale, transcription-related and activity-driven dynamic changes in chromatin fibers may escape structural analyses when employing microscopy techniques, but can be tackled by molecular studies investigating long and short-range chromosomal interactions . This is the case for chromosome conformation capture (CCC or 3C) techniques that are used to analyze the organization of chromosomes in intact cells. Since the invention of this PCR-based technology in 2002 , the emergence of various next-generation sequencing (NGS)-based techniques has dramatically transformed our understating of genome architecture. For example, Hi-C enables CCC studies to be performed on a genomic scale, Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) allows the determination of de novo long-range chromatin interactions genome-wide, and DNase I hypersensitive sites sequencing (DNase-seq), Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE)-seq and Assay for Transposase-Accessible Chromatin (ATAC)-seq allow the assessment of changes in DNA accessibility . These novel NGS techniques in parallel with the aforementioned progress in cell imaging now provide us with an exceptional opportunity to interrogate neuronal chromatin dynamics [33, 35]. For example, FAIRE-seq has revealed major genomic reorganizations during both differentiation and neuronal stimulation , and ulterior Hi-C experiments have shown that topologically-associated domains (TADs) are organized into hierarchical domain-within-domain structures named metaTADs. Some of these metaTADs are remodeled during neuronal maturation while others remain unchanged, thereby supporting stability and at the same time that enabling the adaptability of specific loci .
A key level of genome organization is the movement of genes within the interior of the nucleus. Fundamental contributions in the eighties demonstrated chromosomal movements in seizure foci of the human cortex. These movements were found to affect particularly the X chromosome although they were independent of the patient’s sex . Consistently, the induction of LTP in the hippocampus has been shown to provoke the clustering of satellite DNA in hippocampal neurons . More recent experiments have further elaborated on the details of such chromosomal movements. For instance, in the case of Bdnf, it has been observed that upon kainate-induced seizures there is both a weakening of its interaction with the lamina as well as the relocation of one allele from the nuclear margin to deeper areas within the nucleus . This relocation resulted in the colocalization of Bdnf alleles with poised RNAPII. Intriguingly, the detachment from the lamina persisted beyond the transient increase in transcription, which leaves open the possibility that this structural change could contribute to sensitization of affected neurons for ulterior reactivation . A similar internalization of the Bdnf locus has also been reported to occur in neuronal cultures after depolarization . These movements in the nucleoplasm correlate with the wave of active transcription that follows strong synaptic activation . These gene movements resemble those reported to occur during neuronal differentiation. For example, when neural precursors acquire neuronal commitment, ASCL1 (encoding for the Mash1 protein), along with other proneural genes, move from the nuclear periphery where they remain transcriptionally silent to the central nucleoplasm where they become transcribed [23, 42].
Architectural proteins involved in chromatin loops, and long and short-range interactions
Enhancers are defined as regulatory sequences rich in transcription factor (TF) binding sites that regulate gene activation and are distal to the transcription start site (TSS) . They are often located over 10 Kb from their respective genes, with 22 % of them being found more than 100 Kb away, and are usually identified by their enrichment in H3K4me1 and H3K27ac .
The expression of cell type-specific and brain region-specific genes often relies on enhancer sequences that act specifically only in those cells, while being methylated and inactive elsewhere . Interestingly, these sequences are usually linked to a single promoter [31, 45] and often participate in intricate chromatin loops . Indeed, promoter-enhancer architecture is essential in triggering activity-regulated transcriptional programs. In neurons, about 13,000 enhancers have been identified within a few Kb from TSSs . Luciferase reporter assays have demonstrated productive elongation in these sequences, and led to the identification of enhancer RNAs (eRNA), a special kind of non-coding RNA (ncRNA) whose transcription is initiated near the center of the enhancer sequence . Intriguingly, protein-coding genes associated with eRNAs are highly transcribed, and knocking down the eRNA dampens transcription of the neighboring genes . Indeed, eRNA transcription is a proxy of 3D promoter-enhancer interactions because the release of nascent protein-coding RNA from the promoter needs Negative Elongation Factor (NELF) to bind eRNA and enter into productive elongation . Recent genomic screens aimed to characterize enhancers that mediate activity-dependent transcription in mouse cortical neurons have underscored the importance of the TF Fos, which is itself subjected to regulation by neuronal activation, in the regulation of activity-driven gene programs . In fact, the broad inducibility of Fos in the nervous system seem to rely in the action of at least five enhancers that surround the locus and differentially respond to various stimuli (e.g., membrane depolarization, BDNF binding and adenyl cyclase stimulation) .
Another type of regulatory sequence that relies on chromatin looping are the insulators. Insulators are described as chromatin regions that protect against the activating influence of distal enhancers associated with other genes . The proteins CTCF (aka CCCTC-binding factor), mediator and cohesin are important components of the insulator complex that appear in distinct combinations depending on the range of interaction. CTCF and cohesin locate together in active regulatory sequences where they mediate long-range constitutive interactions. They are fundamental building blocks behind insulated chromosomal neighborhoods containing super-enhancers necessary for cell identity . For instance, the presence of CTCF/cohesin marks megabase-sized TADs whose boundaries are usually constant among all cell types, although there can be cell-type specific subTAD organization . Whereas cohesin is involved in regulation of tissue-specific transcription , CTCF plays a prominent role enabling chromatin looping through the pairing of sequences that contain its binding site [53, 55]. In turn, mediator and cohesin are found in short-range complexes that bridge enhancers and promoters. While mediator is necessary for the loading of enhancers with TFs and the formation of the initiation complex at the promoter , cohesin together with the “loader” protein Nipped-B-like protein (NIPBL) and other factors, brings DNA sequences together forming a ring structure that physically promotes their approximation . The involvement of these proteins in neurodevelopment and cognition is supported by the finding that mutations in the encoding genes cause intellectual disability and severe neurodevelopmental defects (see below). Moreover, experiments in mice indicate that CTCF loss throughout developmental stages has been shown to cause neuronal death and deregulate neuronal differentiation , while ablation in postmitotic neurons caused growth retardation, abnormal hind-paw clasping, defects in somatosensory cortical maps, and reduced dendritic arborization and spine density .
Poised RNAPII and transcription factories
The term transcription factory refers to discrete foci in the eukaryotic nucleus where transcription occurs . These mega-structures promote physical interactions between genes that share the same regulatory machinery, which may enable their synchronous expression . Consistent with this notion, genomic analyses indicate that TF binding can occur in nucleosome-depleted stretches of DNA lacking their canonical binding motifs through the interaction with other TFs and cofactors. Enhancer elements are also thought to form part of these mega transcription factor complexes  that are enriched in cohesin binding and strongly labeled with RNAPII antibodies . It has been described in different immortalized human cell lines that loci highly enriched in RNAPII are often associated with looped chromatin in promoter-promoter interactions (the most common) or in the interactions between promoters and distal regulatory elements . Single-gene complexes show a high intron/exon ratio, include looping conformations between promoters and enhancers, and usually are developmentally regulated and/or tissue-specific. Multigene complexes display interactions among several promoters and often also include enhancers. The genes found in multigene complexes are shorter (i.e., with lower intron/exon ratio), more enriched in GC, and are located in highly transcribed, gene-dense euchromatin regions that are rich in short interspersed nuclear elements (SINEs). Recent genomic studies indicate that, on average, there are more than eight genes per multigene complex , suggesting that promoter-promoter aggregates are a major feature of eukaryotic gene regulation. Such complexes provide the topological basis for common transcriptional regulation of gene groups. For instance, the 58 HIST1H genes located on chromosome 6 are organized into three complexes that further interact to form a larger complex . It is tempting to speculate that poised plasticity-related genes share common transcription factories enriched in the same transcriptional regulators. This could occur through promoter-promoter interactions, which could ultimately synchronize their rapid expression due to higher-order chromatin structures in which RNAPII acts as a primary hub.
Chromatin architecture in neuropsychiatric disease
Neuropsychiatric conditions associated with disrupted nuclear organization and 3D chromatin architecture
Lamin B invaginations
Sig-1R-mediated MaoB repression
Fragile X–associated tremor/ataxia syndrome
Disrupted CBS and speckles
Alpha thalassemia/mental retardation syndrome X
PCDHα enhancer SNP
Cornelia de Lange syndrome
NIPRL, SMC1 and SMC3 mutations
ID, microcephaly and growth retardation
SIRPB1 intronic deletion
Post-traumatic stress disorder/depression
FK506 intronic SNP
Restless Legs syndrome
MEIS1 enhancer SNP
GRIN2B enhancer SNP
Microsatellite repeats in NRG1 intron 1
GAD1 enhancer-promoter dysfunction
Mutations in genes encoding proteins important for nuclear architecture (e.g. CTCF, cohesin and many epigenetic factors) frequently result in neurodevelopmental disorders . This is the case of Opitz-Kaveggia syndrome and Fryns-Lujan syndrome which are both caused by mutations in MED12  that encodes a subunit of the mediator complex. Moreover, mutations in the genes encoding either NIPBL or the cohesin subunits SMC1 and SMC3 cause Cornelia de Lange syndrome , whereas mutations in the CTCF gene have been associated with intellectual disability (ID), microcephaly and growth retardation . Further supporting the link between aberrant chromatin structure and ID, various genes encoding proteins that interact with heterochromatin, such as ATRX and MeCP2, are also linked to ID. Thus, mutations in the gene that encodes ATRX cause Alpha-Thalassemia X-Linked ID syndrome , while the loss of MeCP2 results in Rett syndrome  that manifests itself with ID and autistic traits. Neurons lacking MeCP2 show an abnormal number and size of nucleoli and chromocenters , and an aberrant distribution of pericentric heterochromatinization . Other syndromes are also characterized by nuclear defects even though their etiology is not directly linked to nuclear organizers. For instance, hippocampal neurons with CGG repeat expansions in the FMR1 gene, which give rise to fragile X-associated tremor/ataxia syndrome (FXTAS), accumulate more heterochromatin but in smaller foci .
Another type of genetic disorders associated with abnormal nuclear architecture are laminopathies in which the nuclear lamina is prominently disrupted. This group of disorders includes Hutchinson–Gilford progeria syndrome (HGPS) that is caused by mutations in the gene encoding lamin A . Intriguingly, hippocampal nuclei of mouse models for this condition show abnormal lobulations and deep infoldings of the nuclear envelope, but gene expression and behavioral assays revealed no gross impairment , which indicates that neuronal nuclei can adapt to major perturbations in its structure. In contrast, as we will discuss in further detail for psychiatric conditions, other studies have shown that even local chromatin looping perturbations might lead to neurological symptoms. For example, the single nucleotide polymorphism (SNP) rs12469063 associated with Restless Legs syndrome, a sensorimotor neurological disorder, has been shown to cause looping perturbations and motor restlessness/hyperactivity in mouse models for this condition .
Large-scale chromatin reorganization is often observed in neurons undergoing degeneration. Thus, irregularities in nuclear shape, particularly mediated by B-type lamins, have been described to precede heterochromatin relaxation, DNA damage and neurodegeneration in both Drosophila models of tauopathy and human samples from Alzheimer’s patients . Furthermore, dispersion of the nuclear lamina is known to precede neuronal death and is a common feature seen in mouse models of Alzheimer’s disease . Other alterations may not cause prominent structural changes but still affect function. For example, mouse models for Huntington’s disease (HD) exhibit diminished super-enhancer function of striatum-specific genes governed by Gata2 and display reduced H3K27ac and paused RNAPII binding .
Aberrant chromatin loopings have been recently implicated in psychiatric disorders. For example, Akbarian and colleagues first found that overexpression of the histone methyltransferase Setdb1 caused the heterochromatinization of the promoter of Grin2b (encoding for a subunit of the NMDA receptor) and the loss of a loop tethering the promoter to a Setdb1 target site positioned 30 kb downstream of the TSS . Further investigation of the same locus revealed that the SNP rs117578877, located at the distal arm of another GRIN2B loop, is often found in schizophrenic patients and correlates with impaired working memory and schizotypic features. Notably, isogenic deletions of loop-bound sequences in mice impaired cognitive performance and decreased Grin2b expression . The same team has also reported abnormal chromosomal interactions at a second locus linked to schizophrenia. The formation of a chromatin loop between the TSS of GAD1 (encoding an enzyme critical for GABA synthesis) and an enhancer sequence 50 Kb upstream was found reduced in the prefrontal cortex of schizophrenic patients . A similar loop, sensitive to neuronal activation, was also detected in GABAergic neurons of mice. As a third example, it was recently demonstrated that a polymorphism affecting the interaction between the TSS of FKBP5, which encodes the co-chaperone FK506 binding protein 5, and enhancer sequences located in introns 2 and 7 is associated with an increased risk of developing stress-related psychiatric disorders after childhood trauma . Another recent study has shown that microsatellite repeats in intron 1 of the gene encoding neuregulin 1 (NRG1), a putative schizophrenia susceptibility gene regulating the excitatory-inhibitory balance, are associated with an increase in NRG1 transcripts in the prefrontal cortex, suggesting that this region could function as a transcriptional enhancer. Intriguingly, the presence of these repeats correlated with an earlier age of onset of the symptoms. However, long-range interactions between the intronic sequence and the promoter remain to be experimentally proven . There are additional examples suggesting that abnormalities in chromatin looping may be associated with conditions such a bipolar disorder  and impulsive-disinhibited personality , but molecular studies are still needed to prove the involvement of aberrant chromatin interactions in the etiology of these disorders.
Cause or consequence
Excitingly, the use of engineered transcription factors has recently demonstrated that the local manipulation of epigenetic profiles at a given gene is sufficient to control drug- and stress-evoked transcriptional and behavioral responses, thereby providing seminal evidence for a causative role for those epigenetic marks . Similarly, CRISPR/Cas9 technology now enables direct manipulation of genome topology, opening up the possibility to conduct loss- and gain-of-function experiments exploring the role of altered DNA conformations in pathology and transcription . For example, CRISPR/Cas9 has recently been used to change the orientation of two interacting chromosomal regions, demonstrating that the functionality in vivo of some enhancers carrying CTCF-binding sites relies on their relative orientation and the precise architecture of chromatin domains .
Conclusions and prospects
As reviewed here, numerous studies have illustrated that nuclear architecture and genome topology are key for understanding neuronal function and dysfunction. Changes in subnuclear structures and chromatin loopings have been found to occur in different neuronal plasticity paradigms. Similarly, the disruption of chromatin structures is a landmark for numerous neurological disorders. Although such a disruption likely contributes to the onset of a disorder, a clear distinction between cause and consequence is still missing, except for some monogenic disorders (often associated with ID) caused by mutations in architectural proteins or regulatory sequences. Although the specific contribution of architectural proteins and the changes in 3D chromatin organization to neuroplasticity and neuropathology largely remain to be determined, new light will soon be shed now that novel techniques such as super-resolution microscopy, NGS-based techniques for the analysis of DNA conformation and CRISPR/Cas9-based epi-editing have emerged. These innovative approaches will facilitate a high resolution determination of the 3D organization of the genome, in parallel to a systems-level interrogation of the consequences of gene expression, the identification of loci associated with aberrant function, and even the manipulation of DNA conformations to promote or correct transcriptional changes.
We thank Grzegorz Wilcynski and members of Barco’s lab for critical reading of the manuscript.
AM is recipient of a Formación de Personal Investigador fellowship from the Spanish Ministry of Economy and Competitivity (MINECO). Research in Barco’s lab is supported by grants SAF2014-56197-R, PCIN-2015-192-C02-01 and SEV-2013-0317 from MINECO, grant PROMETEO/2016/006 from the Generalitat Valenciana, a NARSAD Independent Investigator Grant from the Brain & Behavior Research Foundation and a grant from the Alicia Koplowitz Foundation. The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”.
Availability of data and materials
AM elaborated the figures, AM and AB wrote and revised the text. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Takeuchi T, Duszkiewicz AJ, Morris RG. The synaptic plasticity and memory hypothesis: encoding, storage and persistence. Philos Trans R Soc Lond B Biol Sci. 2014;369(1633):20130288.PubMedPubMed CentralView ArticleGoogle Scholar
- Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science. 2001;294(5544):1030–8.PubMedView ArticleGoogle Scholar
- Sweatt JD. The emerging field of neuroepigenetics. Neuron. 2013;80(3):624–32.PubMedView ArticleGoogle Scholar
- Wilczynski GM. Significance of higher-order chromatin architecture for neuronal function and dysfunction. Neuropharmacology. 2014;80:28–33.PubMedView ArticleGoogle Scholar
- Schoenfelder S, Clay I, Fraser P. The transcriptional interactome: gene expression in 3D. Curr Opin Genet Dev. 2010;20(2):127–33.PubMedView ArticleGoogle Scholar
- Berger SL. The complex language of chromatin regulation during transcription. Nature. 2007;447(7143):407–12.PubMedView ArticleGoogle Scholar
- Dekker J. Two ways to fold the genome during the cell cycle: insights obtained with chromosome conformation capture. Epigenetics Chromatin. 2014;7(1):25.PubMedPubMed CentralView ArticleGoogle Scholar
- Aoto T, Saitoh N, Ichimura T, Niwa H, Nakao M. Nuclear and chromatin reorganization in the MHC-Oct3/4 locus at developmental phases of embryonic stem cell differentiation. Dev Biol. 2006;298(2):354–67.PubMedView ArticleGoogle Scholar
- Francastel C, Schübeler D, Martin DI, Groudine M. Nuclear compartmentalization and gene activity. Nat Rev Mol Cell Biol. 2000;1(2):137–43.PubMedView ArticleGoogle Scholar
- Berchtold D, Fesser S, Bachmann G, Kaiser A, Eilert J-C, Frohns F, Sadoni N, Muck J, Kremmer E, Eick D, Layer PG, Zink D. Nuclei of chicken neurons in tissues and three-dimensional cell cultures are organized into distinct radial zones. Chromosome Res. 2011;19(2):165–82.PubMedView ArticleGoogle Scholar
- Croft JA, Bridger JM, Boyle S, Perry P, Teague P, Bickmore WA. Differences in the localization and morphology of chromosomes in the human nucleus. J Cell Biol. 1999;145(6):1119–31.PubMedPubMed CentralView ArticleGoogle Scholar
- Solovei I, Kreysing M, Lanctot C, Kosem S, Peichl L, Cremer T, Guck J, Joffe B. Nuclear architecture of rod photoreceptor cells adapts to vision in mammalian evolution. Cell. 2009;137(2):356–68.PubMedView ArticleGoogle Scholar
- Takizawa T, Meshorer E. Chromatin and nuclear architecture in the nervous system. Trends Neurosci. 2008;31(7):343–52.PubMedView ArticleGoogle Scholar
- Malhas A, Goulbourne C, Vaux DJ. The nucleoplasmic reticulum: form and function. Trends Cell Biol. 2011;21(6):362–73.PubMedView ArticleGoogle Scholar
- Wiegert JS, Bading H. Activity-dependent calcium signaling and ERK-MAP kinases in neurons: a link to structural plasticity of the nucleus and gene transcription regulation. Cell Calcium. 2011;49(5):296–305.PubMedView ArticleGoogle Scholar
- Wittmann M, Queisser G, Eder A, Wiegert JS, Bengtson CP, Hellwig A, Wittum G, Bading H. Synaptic activity induces dramatic changes in the geometry of the cell nucleus: interplay between nuclear structure, histone H3 phosphorylation, and nuclear calcium signaling. J Neurosci. 2009;29(47):14687–700.PubMedView ArticleGoogle Scholar
- Gruenbaum Y, Foisner R. Lamins: Nuclear Intermediate Filament Proteins with Fundamental Functions in Nuclear Mechanics and Genome Regulation. Annu Rev Biochem. 2014. 84 (1):150306093657004–150306093657004.Google Scholar
- Takamori Y, Tamura Y, Kataoka Y, Cui Y, Seo S, Kanazawa T, Kurokawa K, Yamada H. Differential expression of nuclear lamin, the major component of nuclear lamina, during neurogenesis in two germinal regions of adult rat brain. Eur J Neurosci. 2007;25(6):1653–62.PubMedView ArticleGoogle Scholar
- Lee JM, Tu Y, Tatar A, Wu D, Nobumori C, Jung H-J, Yoshinaga Y, Coffinier C, de Jong PJ, Fong LG, Young SG. Reciprocal knock-in mice to investigate the functional redundancy of lamin B1 and lamin B2. Mol Biol Cell. 2014;25(10):1666–75.PubMedPubMed CentralView ArticleGoogle Scholar
- Jung H-J, Nobumori C, Goulbourne CN, Tu Y, Lee JM, Tatar A, Wu D, Yoshinaga Y, de Jong PJ, Coffinier C, Fong LG, Young SG. Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration. Proc Natl Acad Sci U S A. 2013;110(21):E1923–32.PubMedPubMed CentralView ArticleGoogle Scholar
- Zullo JM, Demarco IA, Piqué-Regi R, Gaffney DJ, Epstein CB, Spooner CJ, Luperchio TR, Bernstein BE, Pritchard JK, Reddy KL, Singh H. DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell. 2012;149(7):1474–87.PubMedView ArticleGoogle Scholar
- Dixon JR, Jung I, Selvaraj S, Shen Y, Antosiewicz-Bourget JE, Lee AY, Ye Z, Kim A, Rajagopal N, Xie W, Diao Y, Liang J, Zhao H, Lobanenkov VV, Ecker JR, Thomson JA, Ren B. Chromatin architecture reorganization during stem cell differentiation. Nature. 2015;518(7539):331–6.PubMedPubMed CentralView ArticleGoogle Scholar
- Peric-Hupkes D, Meuleman W, Pagie L, Bruggeman SWM, Solovei I, Brugman W, Gräf S, Flicek P, Kerkhoven RM, van Lohuizen M, Reinders M, Wessels L, van Steensel B. Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol Cell. 2010;38(4):603–13.PubMedView ArticleGoogle Scholar
- Tsai SY, Chuang JY, Tsai MS, Wang XF, Xi ZX, Hung JJ, Chang WC, Bonci A, Su TP. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope. Proc Natl Acad Sci U S A. 2015;112(47):E6562–70.PubMedPubMed CentralView ArticleGoogle Scholar
- Alexander JM, Lomvardas S. Nuclear architecture as an epigenetic regulator of neural development and function. Neuroscience. 2014;264:39–50.PubMedPubMed CentralView ArticleGoogle Scholar
- Jordan BA, Fernholz BD, Khatri L, Ziff EB. Activity-dependent AIDA-1 nuclear signaling regulates nucleolar numbers and protein synthesis in neurons. Nat Neurosci. 2007;10(4):427–35.PubMedGoogle Scholar
- Allen KD, Gourov AV, Harte C, Gao P, Lee C, Sylvain D, Splett JM, Oxberry WC, van de Nes PS, Troy-Regier MJ, Wolk J, Alarcon JM, Hernández AI. Nucleolar integrity is required for the maintenance of long-term synaptic plasticity. PLoS One. 2014;9(8):e104364.PubMedPubMed CentralView ArticleGoogle Scholar
- Hall MH, Magalska A, Malinowska M, Ruszczycki B, Czaban I, Patel S, Ambrożek-Latecka M, Zołocińska E, Broszkiewicz H, Parobczak K, Nair RR, Rylski M, Pawlak R, Bramham CR, Wilczyński GM. Localization and regulation of PML bodies in the adult mouse brain. Brain Struct Funct. 2016;221(5):2511–25.Google Scholar
- Baltanás FC, Casafont I, Lafarga V, Weruaga E, Alonso JR, Berciano MT, Lafarga M. Purkinje cell degeneration in pcd mice reveals large scale chromatin reorganization and gene silencing linked to defective DNA repair. J Biol Chem. 2011;286(32):28287–302.PubMedPubMed CentralView ArticleGoogle Scholar
- Woulfe J. Nuclear bodies in neurodegenerative disease. Biochim Biophys Acta. 2008;1783(11):2195–206.PubMedView ArticleGoogle Scholar
- Zhang Y, Wong C-H, Birnbaum RY, Li G, Favaro R, Ngan CY, Lim J, Tai E, Poh HM, Wong E, Mulawadi FH, Sung W-K, Nicolis S, Ahituv N, Ruan Y, Wei C-L. Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature. 2013;504(7479):306–10.PubMedPubMed CentralView ArticleGoogle Scholar
- Ricci Maria A, Manzo C, García-Parajo MF, Lakadamyali M, Cosma Maria P. Chromatin fibers are formed by heterogeneous groups of nucleosomes in vivo. Cell. 2015;160(6):1145–58.PubMedView ArticleGoogle Scholar
- Risca VI, Greenleaf WJ. Unraveling the 3D genome: genomics tools for multiscale exploration. Trends Genet. 2015;31(7):357–72.PubMedPubMed CentralView ArticleGoogle Scholar
- Dekker J, Rippe K, Dekker M, Kleckner N. Capturing chromosome conformation. Science. 2002;295(5558):1306–11.PubMedView ArticleGoogle Scholar
- Cattoni DI, Valeri A, Le Gall A, Nollmann M. A matter of scale: how emerging technologies are redefining our view of chromosome architecture. Trends Genet. 2015;31(8):454–64.PubMedView ArticleGoogle Scholar
- Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine GG, Krones A, Ohgi KA, Zhu P, Garcia-Bassets I, Liu F, Taylor H, Lozach J, Jayes FL, Korach KS, Glass CK, Fu XD, Rosenfeld MG. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature. 2007;446(7138):882–7.PubMedView ArticleGoogle Scholar
- Fraser J, Ferrai C, Chiariello AM, Schueler M, Rito T, Laudanno G, Barbieri M, Moore BL, Kraemer DC, Aitken S, Xie SQ, Morris KJ, Itoh M, Kawaji H, Jaeger I, Hayashizaki Y, Carninci P, Forrest AR, Consortium F, Semple CA, Dostie J, Pombo A, Nicodemi M. Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation. Mol Syst Biol. 2015;11(12):852.PubMedPubMed CentralView ArticleGoogle Scholar
- Borden J, Manuelidis L. Movement of the X chromosome in epilepsy. Science. 1988;242(4886):1687–91.PubMedView ArticleGoogle Scholar
- Billia F, Baskys A, Carlen PL, De Boni U. Rearrangement of centromeric satellite DNA in hippocampal neurons exhibiting long-term potentiation. Brain Res Mol Brain Res. 1992;14(1–2):101–8.PubMedView ArticleGoogle Scholar
- Walczak A, Szczepankiewicz AA, Ruszczycki B, Magalska A, Zamlynska K, Dzwonek J, Wilczek E, Zybura-Broda K, Rylski M, Malinowska M, Dabrowski M, Szczepinska T, Pawlowski K, Pyskaty M, Wlodarczyk J, Szczerbal I, Switonski M, Cremer M, Wilczynski GM. Novel higher-order epigenetic regulation of the Bdnf gene upon seizures. J Neurosci. 2013;33(6):2507–11.PubMedView ArticleGoogle Scholar
- Crepaldi L, Policarpi C, Coatti A, Sherlock WT, Jongbloets BC, Down TA, Riccio A. Binding of TFIIIC to sine elements controls the relocation of activity-dependent neuronal genes to transcription factories. PLoS Genet. 2013;9(8), e1003699.PubMedPubMed CentralView ArticleGoogle Scholar
- Williams RRE, Azuara V, Perry P, Sauer S, Dvorkina M, Jørgensen H, Roix J, McQueen P, Misteli T, Merkenschlager M, Fisher AG. Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus. J Cell Sci. 2006;119(Pt 1):132–40.PubMedView ArticleGoogle Scholar
- Plank JL, Dean A. Enhancer function: mechanistic and genome-wide insights come together. Mol Cell. 2014;55(1):5–14.PubMedView ArticleGoogle Scholar
- Vermunt MW, Reinink P, Korving J, de Bruijn E, Creyghton PM, Basak O, Geeven G, Toonen PW, Lansu N, Meunier C, van Heesch S, Clevers H, de Laat W, Cuppen E, Creyghton MP. Large-scale identification of coregulated enhancer networks in the adult human brain. Cell Rep. 2014;9(2):767–79.PubMedView ArticleGoogle Scholar
- Kieffer-Kwon K-R, Tang Z, Mathe E, Qian J, Sung M-H, Li G, Resch W, Baek S, Pruett N, Grøntved L, Vian L, Nelson S, Zare H, Hakim O, Reyon D, Yamane A, Nakahashi H, Kovalchuk AL, Zou J, Joung JK, Sartorelli V, Wei C-L, Ruan X, Hager GL, Ruan Y, Casellas R. Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell. 2013;155(7):1507–20.PubMedView ArticleGoogle Scholar
- Fitzpatrick DJ, Ryan CJ, Shah N, Greene D, Molony C, Shields DC. Genome-wide epistatic expression quantitative trait loci discovery in four human tissues reveals the importance of local chromosomal interactions governing gene expression. BMC Genomics. 2015;16(1):109.PubMedPubMed CentralView ArticleGoogle Scholar
- Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, Harmin DA, Laptewicz M, Barbara-Haley K, Kuersten S, Markenscoff-Papadimitriou E, Kuhl D, Bito H, Worley PF, Kreiman G, Greenberg ME. Widespread transcription at neuronal activity-regulated enhancers. Nature. 2010;465(7295):182–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Schaukowitch K, Joo J-Y, Liu X, Watts Jonathan K, Martinez C, Kim T-K. Enhancer RNA Facilitates NELF Release from Immediate Early Genes. Mol Cell. 2014;56(1):29–42.PubMedPubMed CentralView ArticleGoogle Scholar
- Malik AN, Vierbuchen T, Hemberg M, Rubin AA, Ling E, Couch CH, Stroud H, Spiegel I, Farh KK-H, Harmin DA, Greenberg ME. Genome-wide identification and characterization of functional neuronal activity–dependent enhancers. Nat Neurosci. 2014;17(10):1330–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Joo JY, Schaukowitch K, Farbiak L, Kilaru G, Kim TK. Stimulus-specific combinatorial functionality of neuronal c-fos enhancers. Nat Neurosci. 2016;19(1):75–83.PubMedView ArticleGoogle Scholar
- Burgess-Beusse B, Farrell C, Gaszner M, Litt M, Mutskov V, Recillas-Targa F, Simpson M, West A, Felsenfeld G. The insulation of genes from external enhancers and silencing chromatin. Proc Natl Acad Sci U S A. 2002;99 Suppl 4:16433–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Dowen Jill M, Fan Zi P, Hnisz D, Ren G, Abraham Brian J, Zhang Lyndon N, Weintraub Abraham S, Schuijers J, Lee Tong I, Zhao K, Young Richard A. Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes. Cell. 2014;159(2):374–87.PubMedPubMed CentralView ArticleGoogle Scholar
- Phillips-Cremins JE, Sauria MEG, Sanyal A, Gerasimova TI, Lajoie BR, Bell JSK, Ong C-T, Hookway TA, Guo C, Sun Y, Bland MJ, Wagstaff W, Dalton S, McDevitt TC, Sen R, Dekker J, Taylor J, Corces VG. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell. 2013;153(6):1281–95.PubMedPubMed CentralView ArticleGoogle Scholar
- Cuadrado A, Remeseiro S, Graña O, Pisano DG, Losada A. The contribution of cohesin-SA1 to gene expression and chromatin architecture in two murine tissues. Nucleic Acids Res. 2015;43(6):3056–67.PubMedPubMed CentralView ArticleGoogle Scholar
- Handoko L, Xu H, Li G, Ngan CY, Chew E, Schnapp M, Lee CWH, Ye C, Ping JLH, Mulawadi F, Wong E, Sheng J, Zhang Y, Poh T, Chan CS, Kunarso G, Shahab A, Bourque G, Cacheux-Rataboul V, Sung W-K, Ruan Y, Wei C-L. CTCF-mediated functional chromatin interactome in pluripotent cells. Nat Genet. 2011;43(7):630–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, Ebmeier CC, Goossens J, Rahl PB, Levine SS, Taatjes DJ, Dekker J, Young RA. Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010;467(7314):430–5.PubMedPubMed CentralView ArticleGoogle Scholar
- Watson LA, Wang X, Elbert A, Kernohan KD, Galjart N, Bérubé NG. Dual effect of CTCF loss on neuroprogenitor differentiation and survival. J Neurosci. 2014;34(8):2860–70.PubMedView ArticleGoogle Scholar
- Hirayama T, Tarusawa E, Yoshimura Y, Galjart N, Yagi T. CTCF is required for neural development and stochastic expression of clustered Pcdh genes in neurons. Cell Rep. 2012;2(2):345–57.PubMedView ArticleGoogle Scholar
- Melnik S, Deng B, Papantonis A, Baboo S, Carr IM, Cook PR. The proteomes of transcription factories containing RNA polymerases I, II or III. Nat Methods. 2011;8(11):963–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Edelman LB, Fraser P. Transcription factories: genetic programming in three dimensions. Curr Opin Genet Dev. 2012;22(2):110–4.PubMedView ArticleGoogle Scholar
- Li G, Ruan X, Auerbach RK, Sandhu KS, Zheng M, Wang P, Poh HM, Goh Y, Lim J, Zhang J, Sim HS, Peh SQ, Mulawadi FH, Ong CT, Orlov YL, Hong S, Zhang Z, Landt S, Raha D, Euskirchen G, Wei C-L, Ge W, Wang H, Davis C, Fisher-Aylor KI, Mortazavi A, Gerstein M, Gingeras T, Wold B, Sun Y, Fullwood MJ, Cheung E, Liu E, Sung W-K, Snyder M, Ruan Y. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell. 2012;148(1–2):84–98.PubMedPubMed CentralView ArticleGoogle Scholar
- Yan J, Enge M, Whitington T, Dave K, Liu J, Sur I, Schmierer B, Jolma A, Kivioja T, Taipale M, Taipale J. Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites. Cell. 2013;154(4):801–13.PubMedView ArticleGoogle Scholar
- Cisse II, Izeddin I, Causse SZ, Boudarene L, Senecal A, Muresan L, Dugast-Darzacq C, Hajj B, Dahan M, Darzacq X. Real-time dynamics of RNA polymerase II clustering in live human cells. Science (New York, NY). 2013;341(6146):664–7.View ArticleGoogle Scholar
- Kwak H, Lis JT. Control of transcriptional elongation. Annu Rev Genet. 2013;47:483–508.PubMedPubMed CentralView ArticleGoogle Scholar
- Saha RN, Wissink EM, Bailey ER, Zhao M, Fargo DC, Hwang JY, Daigle KR, Fenn JD, Adelman K, Dudek SM. Rapid activity-induced transcription of Arc and other IEGs relies on poised RNA polymerase II. Nat Neurosci. 2011;14(7):848–56.PubMedPubMed CentralView ArticleGoogle Scholar
- Hsieh YJ, Kundu TK, Wang Z, Kovelman R, Roeder RG. The TFIIIC90 subunit of TFIIIC interacts with multiple components of the RNA polymerase III machinery and contains a histone-specific acetyltransferase activity. Mol Cell Biol. 1999;19(11):7697–704.PubMedPubMed CentralView ArticleGoogle Scholar
- Madabhushi R, Gao F, Pfenning Andreas R, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao P-C, Stott Ryan T, Gjoneska E, Nott A, Cho S, Kellis M, Tsai L-H. Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes. Cell. 2015;161(7):1592–605.PubMedPubMed CentralView ArticleGoogle Scholar
- Bjornsson HT. The Mendelian disorders of the epigenetic machinery. Genome Res. 2015;25(10):1473–81.PubMedPubMed CentralView ArticleGoogle Scholar
- Philibert RA, Madan A. Role of MED12 in transcription and human behavior. Pharmacogenomics. 2007;8(8):909–16.PubMedView ArticleGoogle Scholar
- Remeseiro S, Cuadrado A, Kawauchi S, Calof AL, Lander AD, Losada A. Reduction of Nipbl impairs cohesin loading locally and affects transcription but not cohesion-dependent functions in a mouse model of Cornelia de Lange Syndrome. Biochim Biophys Acta. 2013;1832(12):2097–102.PubMedView ArticleGoogle Scholar
- Gregor A, Oti M, Kouwenhoven EN, Hoyer J, Sticht H, Ekici AB, Kjaergaard S, Rauch A, Stunnenberg HG, Uebe S, Vasileiou G, Reis A, Zhou H, Zweier C. De novo mutations in the genome organizer CTCF cause intellectual disability. Am J Hum Genet. 2013;93(1):124–31.PubMedPubMed CentralView ArticleGoogle Scholar
- Ratnakumar K, Bernstein E. ATRX: the case of a peculiar chromatin remodeler. Epigenetics. 2013;8(1):3–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185–8.PubMedView ArticleGoogle Scholar
- Singleton MK, Gonzales ML, Leung KN, Yasui DH, Schroeder DI, Dunaway K, LaSalle JM. MeCP2 is required for global heterochromatic and nucleolar changes during activity-dependent neuronal maturation. Neurobiol Dis. 2011;43(1):190–200.PubMedPubMed CentralView ArticleGoogle Scholar
- Agarwal N, Becker A, Jost KL, Haase S, Thakur BK, Brero A, Hardt T, Kudo S, Leonhardt H, Cardoso MC. MeCP2 Rett mutations affect large scale chromatin organization. Hum Mol Genet. 2011;20(21):4187–95.PubMedView ArticleGoogle Scholar
- Chen Y, Tassone F, Berman RF, Hagerman PJ, Hagerman RJ, Willemsen R, Pessah IN. Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration. Hum Mol Genet. 2010;19(1):196–208.PubMedView ArticleGoogle Scholar
- Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423(6937):293–8.PubMedView ArticleGoogle Scholar
- Baek J-H, Schmidt E, Viceconte N, Strandgren C, Pernold K, Richard TJC, Van Leeuwen FW, Dantuma NP, Damberg P, Hultenby K, Ulfhake B, Mugnaini E, Rozell B, Eriksson M. Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior. Hum Mol Genet. 2015;24(5):1305–21.PubMedView ArticleGoogle Scholar
- Spieler D, Kaffe M, Knauf F, Bessa J, Tena JJ, Giesert F, Schormair B, Tilch E, Lee H, Horsch M, Czamara D, Karbalai N, von Toerne C, Waldenberger M, Gieger C, Lichtner P, Claussnitzer M, Naumann R, Müller-Myhsok B, Torres M, Garrett L, Rozman J, Klingenspor M, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Beckers J, Hölter SM, Meitinger T, Hauck SM, Laumen H, Wurst W, Casares F, Gómez-Skarmeta JL, Winkelmann J. Restless legs syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon. Genome Res. 2014;24(4):592–603.PubMedPubMed CentralView ArticleGoogle Scholar
- Frost B, Bardai FH, Feany MB. Lamin Dysfunction Mediates Neurodegeneration in Tauopathies. Curr Biol. 2016;26(1):129–36.PubMedView ArticleGoogle Scholar
- Chang K-H, Multani PS, Sun K-H, Vincent F, de Pablo Y, Ghosh S, Gupta R, Lee H-P, Lee H-G, Smith MA, Shah K. Nuclear envelope dispersion triggered by deregulated Cdk5 precedes neuronal death. Mol Biol Cell. 2011;22(9):1452–62.PubMedPubMed CentralView ArticleGoogle Scholar
- Achour M, Le Gras S, Keime C, Parmentier F, Lejeune FX, Boutillier AL, Neri C, Davidson I, Merienne K. Neuronal identity genes regulated by super-enhancers are preferentially down-regulated in the striatum of Huntington’s disease mice. Hum Mol Genet. 2015;24(12):3481–96.PubMedView ArticleGoogle Scholar
- Jiang Y, Jakovcevski M, Bharadwaj R, Connor C, Schroeder FA, Lin CL, Straubhaar J, Martin G, Akbarian S. Setdb1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit NR2B. J Neurosci. 2010;30(21):7152–67.PubMedPubMed CentralView ArticleGoogle Scholar
- Bharadwaj R, Peter CJ, Jiang Y, Roussos P, Vogel-Ciernia A, Shen EY, Mitchell AC, Mao W, Whittle C, Dincer A, Jakovcevski M, Pothula V, Rasmussen TP, Giakoumaki SG, Bitsios P, Sherif A, Gardner PD, Ernst P, Ghose S, Sklar P, Haroutunian V, Tamminga C, Myers RH, Futai K, Wood MA, Akbarian S. Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition. Neuron. 2014;84(5):997–1008.PubMedPubMed CentralView ArticleGoogle Scholar
- Bharadwaj R, Jiang Y, Mao W, Jakovcevski M, Dincer A, Krueger W, Garbett K, Whittle C, Tushir JS, Liu J, Sequeira A, Vawter MP, Gardner PD, Casaccia P, Rasmussen T, Bunney Jr WE, Mirnics K, Futai K, Akbarian S. Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia. J Neurosci. 2013;33(29):11839–51.PubMedPubMed CentralView ArticleGoogle Scholar
- Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, Pace TWW, Mercer KB, Mayberg HS, Bradley B, Nemeroff CB, Holsboer F, Heim CM, Ressler KJ, Rein T, Binder EB. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16(1):33–41.PubMedView ArticleGoogle Scholar
- Weickert CS, Tiwari Y, Schofield PR, Mowry BJ, Fullerton JM. Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity. Transl Psychiatry. 2012;2:e104.PubMedPubMed CentralView ArticleGoogle Scholar
- Pedrosa E, Stefanescu R, Margolis B, Petruolo O, Lo Y, Nolan K, Novak T, Stopkova P, Lachman HM. Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia. Schizophr Res. 2008;102(1–3):210–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Laplana M, Royo JL, García LF, Aluja A, Gomez-Skarmeta JL, Fibla J. SIRPB1 copy-number polymorphism as candidate quantitative trait locus for impulsive-disinhibited personality. Genes Brain Behav. 2014;13(7):653–62.PubMedView ArticleGoogle Scholar
- Ito S, Magalska A, Alcaraz-Iborra M, Lopez-Atalaya JP, Rovira V, Contreras-Moreira B, Lipinski M, Olivares R, Martinez-Hernandez J, Ruszczycki B, Lujan R, Geijo-Barrientos E, Wilczynski GM, Barco A. Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction. Nat Commun. 2014;5:4450.PubMedGoogle Scholar
- Heller EA, Cates HM, Pena CJ, Sun H, Shao N, Feng J, Golden SA, Herman JP, Walsh JJ, Mazei-Robison M, Ferguson D, Knight S, Gerber MA, Nievera C, Han MH, Russo SJ, Tamminga CS, Neve RL, Shen L, Zhang HS, Zhang F, Nestler EJ. Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nat Neurosci. 2014;17(12):1720–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Guo Y, Xu Q, Canzio D, Shou J, Li J, Gorkin DU, Jung I, Wu H, Zhai Y, Tang Y, Lu Y, Wu Y, Jia Z, Li W, Zhang MQ, Ren B, Krainer AR, Maniatis T, Wu Q. CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function. Cell. 2015;162(4):900–10.PubMedPubMed CentralView ArticleGoogle Scholar
- Zannas AS, Binder EB. Gene-environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism. Genes Brain Behav. 2014;13(1):25–37.PubMedView ArticleGoogle Scholar
- Holz NE, Buchmann AF, Boecker R, Blomeyer D, Baumeister S, Wolf I, Rietschel M, Witt SH, Plichta MM, Meyer-Lindenberg A, Banaschewski T, Brandeis D, Laucht M. Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume. Brain Struct Funct. 2015;220(3):1355–68.PubMedView ArticleGoogle Scholar