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Lineage-specific reorganization of nuclear peripheral heterochromatin and H3K9me2 domains.

ABSTRACT: Dynamic organization of chromatin within the three-dimensional nuclear space has been postulated to regulate gene expression and cell fate. Here, we define the genome-wide distribution of nuclear peripheral heterochromatin as a multipotent P19 cell adopts either a neural or a cardiac fate. We demonstrate that H3K9me2-marked nuclear peripheral heterochromatin undergoes lineage-specific reorganization during cell-fate determination. This is associated with spatial repositioning of genomic loci away from the nuclear periphery as shown by 3D immuno-FISH. Locus repositioning is not always associated with transcriptional changes, but a subset of genes is upregulated. Mef2c is specifically repositioned away from the nuclear periphery during early neurogenic differentiation, but not during early cardiogenic differentiation, with associated transcript upregulation. Myocd is specifically repositioned during early cardiogenic differentiation, but not during early neurogenic differentiation, and is transcriptionally upregulated at later stages of cardiac differentiation. We provide experimental evidence for lineage-specific regulation of nuclear architecture during cell-fate determination in a mouse cell line.

SUBMITTER: See K

PROVIDER: S-EPMC6382005 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Lineage-specific reorganization of nuclear peripheral heterochromatin and H3K9me2 domains

Project description:Dynamic and regulated organization of chromatin within the 3-dimensional space of the nucleus has been postulated to contribute to gene accessibility, gene expression, and cell fate. Here we define the genome-wide lineage-specific reorganization of nuclear peripheral heterochromatin as a multipotent P19 embryocarcinoma cell adopts either a neural or a cardiac fate. We demonstrate that H3K9me2 marked nuclear peripheral heterochromatin undergoes lineage-specific local reorganization during cell fate determination. Lineage-specific loss of H3K9me2 is associated with spatial repositioning of genomic loci away from the nuclear periphery as shown by high-resolution 3D immuno-fluorescence in situ hybridization (3D immuno-FISH). The lineage-specific repositioning of loci away from the nuclear periphery is not always associated with activation of gene expression, but a subset of these genes is transcriptionally activated. Master regulator Mef2c is specifically repositioned from nuclear periphery during early neurogenic differentiation, but not early cardiogenic differentiation, with associated transcript upregulation. Master regulator Myocd is specifically repositioned during early cardiogenic differentiation, but not early neurogenic differentiation, and is transcriptionally upregulated at later stages of cardiac differentiation. These results provide experimental evidence for lineage-specific regulation of nuclear architecture when the same multipotent progenitor cell adopts distinct fates.

2019-01-24 | GSE121314 | GEO

Lineage-specific reorganization of nuclear peripheral heterochromatin and H3K9me2 domains

Project description:Lineage-specific reorganization of nuclear peripheral heterochromatin and H3K9me2 domains

| PRJNA497049 | ENA

H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis.

Project description:Cell-type-specific 3D organization of the genome is unrecognizable during mitosis. It remains unclear how essential positional information is transmitted through cell division such that a daughter cell recapitulates the spatial genome organization of the parent. Lamina-associated domains (LADs) are regions of repressive heterochromatin positioned at the nuclear periphery that vary by cell type and contribute to cell-specific gene expression and identity. Here we show that histone 3 lysine 9 dimethylation (H3K9me2) is an evolutionarily conserved, specific mark of nuclear peripheral heterochromatin and that it is retained through mitosis. During mitosis, phosphorylation of histone 3 serine 10 temporarily shields the H3K9me2 mark allowing for dissociation of chromatin from the nuclear lamina. Using high-resolution 3D immuno-oligoFISH, we demonstrate that H3K9me2-enriched genomic regions, which are positioned at the nuclear lamina in interphase cells prior to mitosis, re-associate with the forming nuclear lamina before mitotic exit. The H3K9me2 modification of peripheral heterochromatin ensures that positional information is safeguarded through cell division such that individual LADs are re-established at the nuclear periphery in daughter nuclei. Thus, H3K9me2 acts as a 3D architectural mitotic guidepost. Our data establish a mechanism for epigenetic memory and inheritance of spatial organization of the genome.

| S-EPMC6795522 | biostudies-literature

Nuclear pore density controls heterochromatin reorganization during senescence.

Project description:During oncogene-induced senescence (OIS), heterochromatin is lost from the nuclear periphery and forms internal senescence-associated heterochromatin foci (SAHFs). We show that an increased nuclear pore density during OIS is responsible for SAHF formation. In particular, the nucleoporin TPR is necessary for both formation and maintenance of SAHFs. Loss of SAHFs does not affect cell cycle arrest but abrogates the senescence-associated secretory phenotype-a program of inflammatory cytokine gene activation. Our results uncover a previously unknown role of nuclear pores in heterochromatin reorganization in mammalian nuclei and demonstrate the importance of heterochromatin organization for a specific gene activation program.

| S-EPMC6362808 | biostudies-literature

Specifying peripheral heterochromatin during nuclear lamina reassembly.

Project description:A conserved organizational feature of eukaryotic nuclei is the peripheral heterochromatin compartment, which provides a protected area for epigenetically silent genes and gene-poor DNA. In metazoan cells this compartment is associated with the nuclear lamina, the protein meshwork at the inner edge of the nucleus. Heterochromatin-nuclear lamina interactions promote epigenetic gene silencing, which may drive many normal and diseased biological processes. We recently obtained evidence that a previously unstudied human protein, PRR14, participates in the tethering of heterochromatin to the inner nuclear periphery. PRR14 associates with the nuclear lamina and attaches to heterochromatin through its binding partner, heterochromatin protein 1 (HP1). After disassembly early in mitosis, PRR14 reassembles in two steps, first binding to anaphase chromosomes through HP1, followed by association with the nuclear lamina in telophase. PRR14 may thereby play a role in specifying HP1-bound heterochromatin for reattachment to the nuclear lamina at mitotic exit. Here we review the relevant literature, summarize our initial work, and provide additional comments and findings.

| S-EPMC4028353 | biostudies-literature

Arabidopsis AGDP1 links H3K9me2 to DNA methylation in heterochromatin.

Project description:Heterochromatin is a tightly packed form of chromatin that is associated with DNA methylation and histone 3 lysine 9 methylation (H3K9me). Here, we identify an H3K9me2-binding protein, Agenet domain (AGD)-containing p1 (AGDP1), in Arabidopsis thaliana. Here we find that AGDP1 can specifically recognize the H3K9me2 mark by its three pairs of tandem AGDs. We determine the crystal structure of the Agenet domain 1 and 2 cassette (AGD12) of Raphanus sativus AGDP1 in complex with an H3K9me2 peptide. In the complex, the histone peptide adopts a unique helical conformation. AGD12 specifically recognizes the H3K4me0 and H3K9me2 marks by hydrogen bonding and hydrophobic interactions. In addition, we find that AGDP1 is required for transcriptional silencing, non-CG DNA methylation, and H3K9 dimethylation at some loci. ChIP-seq data show that AGDP1 preferentially occupies long transposons and is associated with heterochromatin marks. Our findings suggest that, as a heterochromatin-binding protein, AGDP1 links H3K9me2 to DNA methylation in heterochromatin regions.

| S-EPMC6208443 | biostudies-literature

Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis.

Project description:The linear distribution of genes across chromosomes and the spatial localization of genes within the nucleus are related to their transcriptional regulation. The mechanistic consequences of linear gene order, and how it may relate to the functional output of genome organization, remain to be fully resolved, however. Here we tested the relationship between linear and 3D organization of gene regulation during myogenesis. Our analysis has identified a subset of topologically associated domains (TADs) that are significantly enriched for muscle-specific genes. These lineage-enriched TADs demonstrate an expression-dependent pattern of nuclear organization that influences the positioning of adjacent nonenriched TADs. Therefore, lineage-enriched TADs inform cell-specific genome organization during myogenesis. The reduction of allelic spatial distance of one of these domains, which contains Myogenin, correlates with reduced transcriptional variability, identifying a potential role for lineage-specific nuclear topology. Using a fusion-based strategy to decouple mitosis and myotube formation, we demonstrate that the cell-specific topology of syncytial nuclei is dependent on cell division. We propose that the effects of linear and spatial organization of gene loci on gene regulation are linked through TAD architecture, and that mitosis is critical for establishing nuclear topologies during cellular differentiation.

| S-EPMC4812766 | biostudies-literature

Abo1 is required for the H3K9me2 to H3K9me3 transition in heterochromatin.

Project description:Heterochromatin regulation is critical for genomic stability. Different H3K9 methylation states have been discovered, with distinct roles in heterochromatin formation and silencing. However, how the transition from H3K9me2 to H3K9me3 is controlled is still unclear. Here, we investigate the role of the conserved bromodomain AAA-ATPase, Abo1, involved in maintaining global nucleosome organisation in fission yeast. We identified several key factors involved in heterochromatin silencing that interact genetically with Abo1: histone deacetylase Clr3, H3K9 methyltransferase Clr4, and HP1 homolog Swi6. Cells lacking Abo1 cultivated at 30 °C exhibit an imbalance of H3K9me2 and H3K9me3 in heterochromatin. In abo1∆ cells, the centromeric constitutive heterochromatin has increased H3K9me2 but decreased H3K9me3 levels compared to wild-type. In contrast, facultative heterochromatin regions exhibit reduced H3K9me2 and H3K9me3 levels in abo1∆. Genome-wide analysis showed that abo1∆ cells have silencing defects in both the centromeres and subtelomeres, but not in a subset of heterochromatin islands in our condition. Thus, our work uncovers a role of Abo1 in stabilising directly or indirectly Clr4 recruitment to allow the H3K9me2 to H3K9me3 transition in heterochromatin.

| S-EPMC7142091 | biostudies-literature

Pericentromeric heterochromatin is hierarchically organized and spatially contacts H3K9me2 islands in euchromatin.

Project description:Membraneless pericentromeric heterochromatin (PCH) domains play vital roles in chromosome dynamics and genome stability. However, our current understanding of 3D genome organization does not include PCH domains because of technical challenges associated with repetitive sequences enriched in PCH genomic regions. We investigated the 3D architecture of Drosophila melanogaster PCH domains and their spatial associations with the euchromatic genome by developing a novel analysis method that incorporates genome-wide Hi-C reads originating from PCH DNA. Combined with cytogenetic analysis, we reveal a hierarchical organization of the PCH domains into distinct "territories." Strikingly, H3K9me2-enriched regions embedded in the euchromatic genome show prevalent 3D interactions with the PCH domain. These spatial contacts require H3K9me2 enrichment, are likely mediated by liquid-liquid phase separation, and may influence organismal fitness. Our findings have important implications for how PCH architecture influences the function and evolution of both repetitive heterochromatin and the gene-rich euchromatin.

| S-EPMC7147806 | biostudies-literature

Constitutive heterochromatin reorganization during somatic cell reprogramming.

Project description:Induced pluripotent stem (iPS) cell reprogramming is a gradual epigenetic process that reactivates the pluripotent transcriptional network by erasing and establishing repressive epigenetic marks. In contrast to loci-specific epigenetic changes, heterochromatin domains undergo epigenetic resetting during the reprogramming process, but the effect on the heterochromatin ultrastructure is not known. Here, we characterize the physical structure of heterochromatin domains in full and partial mouse iPS cells by correlative electron spectroscopic imaging. In somatic and partial iPS cells, constitutive heterochromatin marked by H3K9me3 is highly compartmentalized into chromocentre structures of densely packed chromatin fibres. In contrast, chromocentre boundaries are poorly defined in pluripotent embryonic stem and full iPS cells, and are characterized by unusually dispersed 10 nm heterochromatin fibres in high Nanog-expressing cells, including pluripotent cells of the mouse blastocyst before differentiation. This heterochromatin reorganization accompanies retroviral silencing during conversion of partial iPS cells by MEK/GSK3 2i inhibitor treatment. Thus, constitutive heterochromatin is compacted in partial iPS cells but reorganizes into dispersed 10 nm chromatin fibres as the fully reprogrammed iPS cell state is acquired.

| S-EPMC3102001 | biostudies-literature

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