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Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction [expression]

ABSTRACT: The interior of the eukaryotic cell nucleus is a highly organized 3D structure. In mature hippocampal and cortical pyramidal neurons, transcriptionally silent DNA is typically compacted in a few clusters referred to as chromocenters that are strongly stained with DNA intercalating agents like DAPI and whose function is still uncertain. We found that this 3D structure was severely disrupted by the incorporation of the chimeric histone H2BGFP into neuronal chromatin. Experiments in inducible and forebrain restricted bitransgenic mice demonstrated that the expression of this histone alters the higher-order organization of neuronal heterochromatin and causes a complex behavioral phenotype that includes hyperactivity, and social interaction, prepulse inhibition and cognitive defects. This phenotype was associated with highly specific transcriptional deficits that affected several serotonin receptor genes located at the edge of gene desert regions. Pharmacological and electrophysiological experiments indicate that this epigenetically-induced hyposerotonergic state may underlie the behavioral defects. Our results suggest a new role for perinuclear heterochromatin and chromocenter organization in the epigenetic regulation of neuronal gene expression and mental illness. We used microarrays to detect differential gene expression in transgenic mice expressing histone H2BGFP in the forebrain.

ORGANISM(S): Mus musculus

PROVIDER: GSE48437 | GEO | 2014/07/18

SECONDARY ACCESSION(S): PRJNA210143

REPOSITORIES: GEO

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Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction

Project description:The interior of the eukaryotic cell nucleus is a highly organized 3D structure. In mature hippocampal and cortical pyramidal neurons, transcriptionally silent DNA is typically compacted in a few clusters referred to as chromocenters that are strongly stained with DNA intercalating agents like DAPI and whose function is still uncertain. We found that this 3D structure was severely disrupted by the incorporation of the chimeric histone H2BGFP into neuronal chromatin. Experiments in inducible and forebrain restricted bitransgenic mice demonstrated that the expression of this histone alters the higher-order organization of neuronal heterochromatin and causes a complex behavioral phenotype that includes hyperactivity, and social interaction, prepulse inhibition and cognitive defects. This phenotype was associated with highly specific transcriptional deficits that affected several serotonin receptor genes located at the edge of gene desert regions. Pharmacological and electrophysiological experiments indicate that this epigenetically-induced hyposerotonergic state may underlie the behavioral defects. Our results suggest a new role for perinuclear heterochromatin and chromocenter organization in the epigenetic regulation of neuronal gene expression and mental illness. We used microarrays to detect differential gene expression in transgenic mice expressing histone H2BGFP in the forebrain. We obtained triplicate samples (biological replicates) of either genotype (wild-type and H2BGFP mice). Each sample contained pooled total RNA from the hippocampi of 2 three-month old genotype-matched mice.

2014-07-18 | E-GEOD-48437 | biostudies-arrayexpress

Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction [ChIP-seq]

Project description:The interior of the neuronal cell nucleus is a highly organized 3-dimensional (3D) structure in which regions of the genome that are millions of bases apart participate in specialized sub-structures with dedicated functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice that express histone GFP-tagged H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons causes chromocenter declustering and disrupts the association of heterochromatin with the nuclear lamina. The loss of these structures does not affect neuronal viability but is associated with specific transcriptional and behavioral deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D-organization of chromatin in the neuronal nucleus supports an additional level of epigenetic regulation of gene expression that critically influences neuronal function and indicate that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture. Genome-wide profiling by high throughput sequencing of H3K27me3 in the adult hippocampus of CaMKII-tTA/tetO-H2BGFP (H2BGFP) and their wild-type littermates mice (WT). Chromatin immunoprecipitation (ChIP) was carried out using pooled hippocampal tissue from 3 mice (one hippocampus per mouse). One DNA library was constructed per genotype. Each DNA library was prepared from pooled immunoprecipitated DNA from 4 independent ChIP assays. In total, tissue from 12 different mice was used to prepare each DNA library. 60% of a lane was used to perform single end (1x50bp) multiplex sequencing in HiSeq 2500 apparatus (Illumina). Each library, was sequenced in duplicate (in two independent sequencing runs. Technical replicates).

2014-07-18 | E-GEOD-56809 | biostudies-arrayexpress

Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction [ChIP-seq]

2014-07-18 | GSE56809 | GEO

CHARACTERIZATION AND DYNAMICS OF MOUSE PERICENTROMERE-ASSOCIATED DOMAINS

Project description:Despite recent progress in genome topology knowledge, the role of repeats, comprising the majority of mammalian genomes, remains elusive. Satellites are highly abundant sequences that cluster around centromeres, attract pericentromeric heterochromatin and aggregate into nuclear chromocenters that are assumed to form a repressive compartment in the nucleus to which genes are recruited for silencing. Here we designed a strategy for genome-wide identification of pericentromere-associated domains (PADs) in different mouse cell types. The ~1000 PADs and non-PADs have similar chromatin states in embryonic stem cells. During lineage commitment however chromocenters progressively overlap with constitutively inactive genomic regions at the nuclear periphery. This suggests that chromocenters do not actively recruit PADs but are themselves attracted to inactive chromatin compartments. However, we also found that experimentally induced proximity of an active locus to chromocenters was sufficient to cause gene repression. Collectively, our data suggests that rather than being a driver of nuclear organization, pericentromeric satellite repeats mostly co-segregate with inactive genomic regions to nuclear compartments where they can contribute to stably maintaining the repressed status of proximal chromosomal regions. We performed satellite 4C (sat4C) on mouse primary thymus tissue, pluripotent mouse embryonic stem cells (ESC) and neural precursor cells (NPC) and terminally differentiated astrocytes (AC) that were sequentially derived from these ESC in vitro

2015-04-01 | E-GEOD-65618 | biostudies-arrayexpress

Evolutional heterochromatin condensation delineates chromocenter formation and retrotransposon constraint in plants

Project description:Heterochromatic condensates (chromocenters) are critical for maintaining the silencing of heterochromatin. However, it is a riddle why the presence of chromocenters is variable across species. Here, we reveal that variations in the plant heterochromatin protein ADCP1 confer a diversity in chromocenter formation via phase separation. ADCP1 physically interacts with the high mobility group protein HMGA to form a complex and mediates heterochromatin condensation by multivalent interactions. The loss of intrinsically disordered regions (IDRs) in ADCP1 homologues during evolution has led to the absence of prominent chromocenter in various plant species, and introduction of IDR-containing ADCP1 with HMGA promotes heterochromatin condensation and retrotransposon silencing. Moreover, plants in the Cucurbitaceae group have evolved an IDR-containing chimera of ADCP1 and HMGA, which enables formation of chromocenters remarkably. Together, our work uncovers a coevolved mechanism of phase separation in packing heterochromatin and constraining retrotransposons.

2024-06-22 | GSE233265 | GEO

Expression data from mouse myogenic differentiation and ectopic MeCP2

Project description:The methyl-cytosine binding protein 2 (MeCP2) is a reader of epigenetic DNA methylation marks and necessary and sufficient to reorganize 3D heterochromatin structure during cellular differentiation, e.g., myogenesis. In addition to global expression profile changes, myogenic differentiation is accompanied by 3D-heterochromatin reorganization that is dependent on MeCP2. MeCP2 is enriched at pericentric heterochromatin foci (chromocenters). During myogenesis, the total heterochromatin foci number per nucleus decreases while foci volumes and MeCP2 protein levels increase. Ectopic MeCP2 is able to mimic similar heterochromatin restructuring in the absence of differentiation. We compared expression profile changes during myogenic differentiation to changes related to MeCP2-induced heterochromatin reorganization in the absence of differentiation. We used the Affymetrix 430.2 microarray system to study the expression profile changes during myogenic differentiation (myotubes vs myoblast) and MeCP2 related expression changes in transiently transfected myoblasts (high vs. low MeCP2 protein levels) in five independent experiments for each condition.

2015-08-15 | GSE69087 | GEO

CHARACTERIZATION AND DYNAMICS OF MOUSE PERICENTROMERE-ASSOCIATED DOMAINS

2015-04-01 | GSE65618 | GEO

Heterochromatic 3D genome organization is directed by HP1a and H3K9-dependent and independent mechanisms[CUT&RUN]

Project description:Whether and how histone post-translational modifications and the proteins that bind them drive 3D genome organization remains unanswered. Here, we evaluate the contribution of H3K9-methylated constitutive heterochromatin to 3D genome organization in Drosophila tissues. We find that the predominant organizational feature of wildtype tissues is segregation of euchromatic chromosome arms from heterochromatic pericentromeres. Reciprocal perturbation of HP1a•H3K9me binding, using a point mutation in the HP1a chromodomain or replacement of the replication-dependent histone H3 with H3K9R mutant histones, revealed that HP1a binding to methylated H3K9 in constitutive heterochromatin is required to limit contact frequency between pericentromeres and chromosome arms and regulate the distance between arm and pericentromeric regions. Surprisingly, self-association of pericentromeric regions is largely preserved despite loss of H3K9 methylation and HP1a occupancy. Thus, the HP1a•H3K9 interaction contributes to, but does not solely drive, segregation of euchromatin and heterochromatin inside the nucleus.

2024-05-24 | GSE236964 | GEO

Mus musculus

Project description:Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction [expression]

| PRJNA210143 | ENA

SMARCAD1 and TOPBP1 contribute to heterochromatin maintenance at the transition from the 2C-like to the pluripotent state

Project description:Chromocenters are established after the 2-cell (2C) stage during mouse embryonic development, but the factors that mediate chromocenter formation remain largely unknown. To identify regulators of 2C heterochromatin establishment, we generated an inducible system to convert embryonic stem cells (ESCs) to 2C-like cells. This conversion is marked by a global reorganization and dispersion of H3K9me3-heterochromatin foci, which are then reversibly formed upon re-entry into pluripotency. Profiling the chromatin-bound proteome (chromatome) by genome capture of ESCs transitioning to 2C-like cells, we uncover chromatin regulators involved in de novo heterochromatin formation. We identified TOPBP1 and investigated its binding partner SMARCAD1. SMARCAD1 and TOPBP1 associate with H3K9me3-heterochromatin in ESCs. Interestingly, the nuclear localization of SMARCAD1 is lost in 2C-like cells. SMARCAD1 or TOPBP1 depletion in mouse embryos lead to developmental arrest, reduction of H3K9me3 and remodeling of heterochromatin foci. Collectively, our findings contribute to comprehending the maintenance of chromocenters during early development.

2023-04-18 | PXD019703 | Pride

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