Confined Migration Induces Heterochromatin Formation and Alters Chromatin Accessibility
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE181247 | GEO | 2022/08/10
REPOSITORIES: GEO
Similar Datasets
Project description:Confined Migration Induces Heterochromatin Formation and Alters Chromatin Accessibility
| PRJNA751211 | ENA
Project description:Heterochromatin spreading leads to the silencing of genes within its path, and boundary elements have evolved to constrain such spreading. In fission yeast, heterochromatin at centromeres I and III is flanked by inverted repeats termed IRCs, which are required for proper boundary functions. However, the mechanisms by which IRCs prevent heterochromatin spreading are unknown. Here, we identified Bdf2, homologous to the mammalian BET family of double bromodomain proteins involved in diverse types of cancers, as a factor required for proper boundary function at IRCs. Bdf2 is enriched at IRCs through its interaction with the boundary protein Epe1. The bromodomains of Bdf2 recognize acetylated histone H4 tails and antagonize Sir2-mediated deacetylation of histone H4K16 to prevent heterochromatin spreading. Our results thus illustrate a mechanism of establishing chromosome boundaries at specific sites through the recruitment of a factor that protects euchromatic histone modifications. They also reveal a previously unappreciated function of H4K16 acetylation, which cooperates with H3K9 methylation to regulate heterochromatin spreading. Two samples, H4K16ac & Bdf2-Flag
2013-09-24 | E-GEOD-46430 | biostudies-arrayexpress
Project description:In budding yeast, telomeres and the mating type (HM) loci are found in a heterochromatin-like silent structure initiated by Rap1 and extended by the interaction of Sir (Silencing Information Regulator) proteins with histones. Binding data demonstrate that both the H3 and H4 N terminal domains required for silencing in vivo interact directly with Sir3 and Sir4 in vitro. The role of H4 lysine 16 deacetylation is well established in Sir3 protein recruitment, however that of the H3 N terminal tail has remained unclear. In order to characterize the role of H3 in silent chromatin formation and compare it to H4 we have generated comprehensive high resolution genome-wide binding maps of heterochromatin proteins. We find that H4 lysine 16 deacetylation is required for the recruitment and spreading of heterochromatin proteins at all telomeres and HM loci. In contrast the H3 N terminus is required for neither recruitment nor spreading of Sir proteins. Instead, deletion of the H3 tail leads to increased accessibility within heterochromatin of an ectopic bacterial dam methylase and the decreased mobility of an HML heterochromatic fragment in sucrose gradients. These findings indicate an altered chromatin structure. We propose that Sir proteins recruited by the H4 tail then interact with the H3 tail to form a higher order silent chromatin structure.
2009-08-01 | GSE16742 | GEO
Project description:Heterochromatin spreading leads to the silencing of genes within its path, and boundary elements have evolved to constrain such spreading. In fission yeast, heterochromatin at centromeres I and III is flanked by inverted repeats termed IRCs, which are required for proper boundary functions. However, the mechanisms by which IRCs prevent heterochromatin spreading are unknown. Here, we identified Bdf2, homologous to the mammalian BET family of double bromodomain proteins involved in diverse types of cancers, as a factor required for proper boundary function at IRCs. Bdf2 is enriched at IRCs through its interaction with the boundary protein Epe1. The bromodomains of Bdf2 recognize acetylated histone H4 tails and antagonize Sir2-mediated deacetylation of histone H4K16 to prevent heterochromatin spreading. Our results thus illustrate a mechanism of establishing chromosome boundaries at specific sites through the recruitment of a factor that protects euchromatic histone modifications. They also reveal a previously unappreciated function of H4K16 acetylation, which cooperates with H3K9 methylation to regulate heterochromatin spreading.
2013-09-24 | GSE46430 | GEO
Project description:Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. In higher eukaryotes, constitutive heterochromatin is mostly segregated at the nuclear periphery, where the interaction with the nuclear lamina makes the genome more resistant to transcription. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here we show that LINE-1 (L1) RNA accumulation is an early event in both typical and atypical progeroid syndromes. Depletion of L1 RNA in cells from different progeroid syndrome patients using specific antisense oligonucleotides (ASO) restores the levels of heterochromatin epigenetic marks, reverses DNA methylation age and counteracts the expression of senescence-associated genes. Moreover, proteome profiling involved in senescence phenotype was partially restored upon depletion of LINE-1 RNA in both Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner syndrome (WRN-/-).
2022-11-02 | PXD032944 | Pride
Project description:A large portion of the mammalian genome is assembled into constitutive heterochromatin which is highly compact and transcriptionally silent throughout the cell cycle. On the molecular level it is characterized by DNA methylation, “repressive” histone marks (hypoacethylation, H3K9 trimethylation, H4K20 trimethylation) and the presence of heterochromatin protein 1 (HP1). Regions of constitutive heterochromatin such as telomeres, pericentromeres and centromeres play a critical role in the maintenance of the genome integrity. Using a technique called Proteomics of Isolated Chromatin Segments (PICh) we have identified SMCHD1 as a novel component of telomeres and pericentomeres. SMCHD1 was previously shown to be involved in the inactivaction of the X chromosome and imprinting, but the its exact role in these processes is not understood. Our study aims to unravel the role of SMCHD1 in the formation and/or maintenance of constitutive chromatin. Using human cancer cells as research model we are trying to discover its mechanism of action by identifying its interacting partners, characterizing its genome wide binding sites and characterizing the effect of SMCHD1 knockout on the heterochromatin function. Characterization of SMCHD1 binding sites in HCT-116 cells.
2015-05-01 | E-GEOD-46462 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Repetitive sequences such as telomeres, centromeres, and retrotransposons are packed in permanently-condensed and transcriptionally-silenced heterochromatin, whose maintenance is critical for the genome stability. We have recently found that mouse ES cells occasionally go through a unique cell state marked by the transient expression of Zscan4, which plays a key role in long-term genome stability. Here we report our unexpected and counterintuitive finding that the Zscan4+ state is accompanied by a Zscan4-mediated rapid activation and repression of heterochromatin: the burst of transcription from heterochromatin coincided with its transient histone hyperacetylation and DNA demethylation, the clustering of pericentromeric heterochromatin in the perinucleolar region, and the accumulation of chromatin remodeling complexes for both activation (HATs, SWI/SNF) and repression (HDACs, LSD1/KDM1A, NuRD) on heterochromatin. Overall, these findings suggest that ES cells maintain their extraordinary genome stability and immortality by transiently taking extreme measures – a usually forbidden transition to the activated state of heterochromatin. Refer to individual Series
2015-09-10 | E-GEOD-51682 | biostudies-arrayexpress
Project description:Domains of heterochromatin play important roles in the maintenance and regulation of eukaryotic genomes. However, the repressive nature of heterochromatin combined with its propensity to self-propagate necessitates the existence of robust mechanisms that limit heterochromatin spreading and thereby avoid silencing of expressed genes. A number of specific sequence elements have been found to serve as barriers to heterochromatin spreading; however, the mechanisms by which spreading is curtailed are generally not well understood. Here we uncover a role for PAF complex component Leo1 in regulating heterochromatin cis-spreading. A genetic screen revealed that loss of Leo1 results in spreading of heterochromatin across a centromeric (IRC) boundary element in fission yeast. Similar heterochromatin spreading was seen upon deletion of other components of the PAF complex, but not other factors involved in transcription-coupled chromatin modification, indicating a specific role for the PAF complex in heterochromatin regulation. Loss of Leo1 is associated with reduced levels of H4K16 acetylation at the boundary, while tethering of the H4K16 acetyltransferase Mst1 to boundary chromatin suppresses heterochromatin spreading in leo1? cells, suggesting that Leo1 antagonises heterochromatin spreading by facilitating H4K16 acetylation. Interestingly, Leo1 also regulates heterochromatin spreading independently of boundaries, and loss of Leo1 causes redistribution of heterochromatin, in particular resulting in substantial expansion of telomeric heterochromatin domains. The PAF complex is known to be an important regulator of transcription-related chromatin modifications; our findings reveal a previously undescribed role for this complex in global regulation of heterochromatin spreading in cis. 8 samples: input (whole cell extract) and IP from H3K9me2 ChIP in wild-type and leo1? cells, in duplicate
2015-05-22 | E-GEOD-61688 | biostudies-arrayexpress
Project description:Purpose: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and infiltration of leukemic cells is critical for disease progression and relapse. In spite of the canonical functions of epigenetics in transcription and DNA homeostasis, its contribution to the nuclear deformability of migrating leukemic cells remains unclear. The objective was to evaluate the role of WDR5 (a core subunit of the histone H3K4 methyltransferases) during leukemia cell migration. Experimental design: We used ALL cell lines and primary samples from patients to study their response and migration in 3D environments and how they extravasate in a mouse xenograft model. We also performed, biophysical, transcriptional and ChIP-sequencing analyses to determine the mechanism by which WDR5 controls ALL progression. Results: We observed that WDR5 activity is critical for ALL cell invasion into 3D collagen matrices. Notably, blocking WDR5 activity also decreased the extravasation of ALL cells in an in vivo model. We identified that 3D constrained conditions promoted H3K4 methylation in ALL cells that altered the global chromatin configuration and transcriptional changes related to cell cycle and DNA replication. WDR5 inhibition did not impair cell adhesion or cell response to chemokines; but we demonstrated that 3D conditions affected the deformation and biophysical behavior of the nucleus in ALL cells. Conclusions: We conclude that confined conditions have a fundamental role in ALL cell biology and provide novel molecular and biophysical mechanisms used by leukemia cells to disseminate. Targeting WDR5 might be a promising therapeutic strategy against ALL infiltration and dissemination.
2024-01-14 | GSE193383 | GEO
Project description:Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. In higher eukaryotes, constitutive heterochromatin is mostly segregated at the nuclear periphery, where the interaction with the nuclear lamina makes the genome more resistant to transcription. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here we show that LINE-1 (L1) RNA accumulation is an early event in both typical and atypical progeroid syndromes. L1 RNA negatively regulates Suv39H1 enzymatic activity, resulting in heterochromatin loss and onset of senescent phenotypes. Depletion of L1 RNA in cells from different progeroid syndrome patients using specific antisense oligonucleotides (ASO) restores the levels of heterochromatin epigenetic marks, preserves DNA methylation and counteracts the expression of senescence-associated genes. Moreover, systemic delivery of ASO rescues the histophysiology of all tissues and increases the lifespan of Hutchinson-Gilford Progeria Syndrome (HGPS) mouse model. Furthermore, the transcriptional profiling following L1 RNA depletion shows that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response and DNA damage were downregulated. Our results show a key role of L1 RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.
2022-08-24 | GSE198675 | GEO