The loss of heterochromatin is associated with multiscale three-dimensional genome reorganization and aberrant transcription during cellular senescence
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ABSTRACT:
PROVIDER: PRJNA551006 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11016356_1.fastq.gz | Fastqsanger.gz | |||
| SRR11016356_2.fastq.gz | Fastqsanger.gz | |||
| SRR11016357_1.fastq.gz | Fastqsanger.gz | |||
| SRR11016357_2.fastq.gz | Fastqsanger.gz | |||
| SRR11016358_1.fastq.gz | Fastqsanger.gz |
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Project description:Heterochromatin remodeling is critical for various cell processes. In particular, the “loss of heterochromatin” phenotype in cellular senescence engages with the progress of aging and age-related disorders. Although biological processes of senescent cells including senescence-associated heterochromatin foci (SAHF) formation, chromosome compaction and entry into senescence have been closely associated with high-order chromatin structure. the relationship between the high-order chromatin organization and the loss of heterochromatin phenotype during senescence has not been fully understood. By using senescent and late senescent fibroblasts induced by DNA damage harboring the “loss of heterochromatin” phenotype, we observed progressive 3D reorganization of heterochromatin during senescence. Facultative and constitutive heterochromatin marked by H3K27me3 and H3K9me3, respectively, showed different alterations. Facultative heterochromatin tends to switch from the repressive B-compartment to the active A-compartment, whereas constitutive heterochromatin shows no significant changes at the compartment level but enhanced interactions between themselves. Interestingly, both types show increased chromatin accessibility and gene expression leakage during senescence. Furthermore, increased chromatin accessibility in potential CTCF binding sites accompanies by the establishment of novel loops in constitutive heterochromatin. Finally, we also observed aberrant expression of repetitive elements, including LTR (long terminal repeat) and satellite classes. Overall, facultative and constitutive heterochromatin show multiscale but distinct alterations in the 3D map, meanwhile they also share the same features of increased chromatin accessibility and gene expression leakage. This study provides an epigenomic map of heterochromatin reorganization during senescence.
2019-12-31 | GSE133292 | GEO
Project description:Heterochromatin remodeling is critical for various cell processes. In particular, the "loss of heterochromatin" phenotype in cellular senescence is associated with the process of aging and age-related disorders. Although biological processes of senescent cells, including senescence-associated heterochromatin foci (SAHF) formation, chromosome compaction, and redistribution of key proteins, have been closely associated with high-order chromatin structure, the relationship between the high-order chromatin reorganization and the loss of heterochromatin phenotype during senescence has not been fully understood. By using senescent and deep senescent fibroblasts induced by DNA damage harboring the "loss of heterochromatin" phenotype, we observed progressive 3D reorganization of heterochromatin during senescence. Facultative and constitutive heterochromatin marked by H3K27me3 and H3K9me3, respectively, show different alterations. Facultative heterochromatin tends to switch from the repressive B-compartment to the active A-compartment, whereas constitutive heterochromatin shows no significant changes at the compartment level but enhanced interactions between themselves. Both types of heterochromatin show increased chromatin accessibility and gene expression leakage during senescence. Furthermore, increased chromatin accessibility in potential CTCF binding sites accompanies the establishment of novel loops in constitutive heterochromatin. Finally, we also observed aberrant expression of repetitive elements, including LTR (long terminal repeat) and satellite classes. Overall, facultative and constitutive heterochromatin show both similar and distinct multiscale alterations in the 3D map, chromatin accessibility, and gene expression leakage. This study provides an epigenomic map of heterochromatin reorganization during senescence.
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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.
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Project description:Crucial mechanisms are required to restrict self-propagating heterochromatin spreading within defined boundaries and prevent euchromatic gene silencing. In the filamentous fungus Neurospora crassa, the JmjC domain protein DNA METHYLATION MODULATOR-1 (DMM-1) prevents aberrant spreading of heterochromatin, but the molecular details remain unknown. Here, we revealed that DMM-1 is highly enriched in a well-defined 5-kb heterochromatin domain and constrained its aberrant spreading. Interestingly, aberrant spreading of the 5-kb heterochromatin domain observed in the dmm-1KO strain is accompanied by the sharp deposition of histone variant H2A.Z, and deletion of H2A.Z abolishes aberrant spreading of the 5-kb heterochromatin domain into adjacent euchromatin. Furthermore, lysine 56 of histone H3 is deacetylated at the expanded heterochromatin regions, and mimicking H3K56 acetylation with an H3K56Q mutation effectively blocks H2A.Z-mediated aberrant spreading of the 5-kb heterochromatin domain. More importantly, genome-wide analyses demonstrated the general roles of H3K56 deacetylation and H2A.Z deposition in aberrant spreading of heterochromatin. Altogether, our results illustrate a previously unappreciated regulatory process that mediates aberrant heterochromatin spreading.
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Project description:The centromere is essential for the inheritance of genetic information on eukaryotic chromosomes. Epigenetic regulation of centromere identity has been implicated in genome stability, karyotype evolution and speciation. However, little is known regarding the manner in which centromere dysfunction affects the chromosomal architectures. Here we show that in the fission yeast Schizosaccharomyces pombe, the conditional deletion of the centromere produces survivors that carry either neocentromere-acquired chromosome at the sub-telomeric region or acentric chromosome rescued by inter-telomere fusion with other chromosome. The ratio of neocentromere formation to telomere fusion is considerably decreased by inactivation of genes involved in RNA interference (RNAi)-dependent heterochromatin formation. By affecting the modes of chromosomal reorganization, the genomic distribution of heterochromatin may influence the fate of karyotype evolution. Keywords: ChIP-chip
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Project description:Lineage-specific reorganization of nuclear peripheral heterochromatin and H3K9me2 domains
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Project description:Heterochromatin is a specialized form of chromatin that restricts access to DNA and inhibits genetic processes, including transcription and recombination. In Neurospora crassa, constitutive heterochromatin is characterized by trimethylation of lysine 9 on histone H3, hypoacetylation of histones, and DNA methylation. Here we explore whether the conserved histone demethylase, lysine-specific demethylase 1 (LSD1), regulates heterochromatin in Neurospora, and if so, how. Though LSD1 is implicated in heterochromatin regulation, its function is inconsistent across different systems; orthologs of LSD1 have been shown to either promote or antagonize heterochromatin expansion by removing H3K4me or H3K9me respectively. We identify three members of the Neurospora LSD complex (LSDC): LSD1, PHF1, and BDP-1, and strains deficient for any exhibit variable spreading of heterochromatin and establishment of new heterochromatin domains dispersed across the genome. Heterochromatin establishment outside of canonical domains in Neurospora share the unusual characteristic of DNA methylation-dependent H3K9me3; typically, H3K9me3 establishment is independent of DNA methylation. Consistent with this, the hyper-H3K9me3 phenotype of LSD1 knock-out strains is dependent on the presence of DNA methylation, as well as HCHC-mediated histone deacetylation, suggesting spreading is dependent on some feedback mechanism. Altogether, our results suggest LSD1 works in opposition to HCHC to maintain proper heterochromatin boundaries.
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