Confined Migration Induces Heterochromatin Formation and Alters Chromatin Accessibility
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ABSTRACT:
PROVIDER: PRJNA751211 | ENA |
REPOSITORIES: ENA
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Project description:We show that confined migration results in predominantly decreased chromatin accessibility, consistent with the increased heterochromatin marks staining. A small fraction of ATAC-seq peaks shows increased accessibility at gene promoters of diverse pathways, such as chromatin silencing, tumor invasion, and DNA damage response; whereas the majority shows decreased accessibility at intergenic regions near centromeres or telomeres, suggesting possible heterochromatin spreading.
2022-08-10 | GSE181247 | GEO
Project description:During migration, cells often squeeze through small constrictions, requiring extensive deformation. We hypothesized that nuclear deformation associated with such confined migration could alter chromatin organization and function. By studying cells migrating through microfluidic devices that mimic interstitial spaces in vivo, we found that confined migration results in increased H3K9me3 and H3K27me3 heterochromatin marks that persist for days. This "confined migration-induced heterochromatin" (CMiH) was distinct from heterochromatin formation during migration initiation. Confined migration decreased chromatin accessibility at intergenic regions near centromeres and telomeres, suggesting heterochromatin spreading from existing sites. Consistent with the overall decrease in accessibility, global transcription was decreased during confined migration. Intriguingly, we also identified increased accessibility at promoter regions of genes linked to chromatin silencing, tumor invasion, and DNA damage response. Inhibiting CMiH reduced migration speed, suggesting that CMiH promotes confined migration. Together, our findings indicate that confined migration induces chromatin changes that regulate cell migration and other functions.
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Project description:WDR5 activity regulates nuclear changes and migration of acute lymphoblastic leukemia cells across confined spaces.
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Project description:Nucleosome turnover concomitant with incorporation of the replication-independent histone variant H3.3 is a hallmark of regulatory regions in the animal genome. In our current understanding, nucleosome turnover is universally linked to DNA accessibility and histone acetylation. In mouse embryonic stem cells, H3.3 is also highly enriched at interstitial heterochromatin, most prominently intracisternal-A particle endogenous retroviral elements. Interstitial heterochromatin is established over confined domains by the TRIM28/SETDB1 corepressor complex and has stereotypical features of repressive chromatin, such as H3K9me3 and recruitment of all HP1 isoforms. Here, we demonstrate that fast histone turnover and H3.3 incorporation is compatible with these hallmarks of heterochromatin. We identify Smarcad1 to be a chromatin remodeler that generates nucleosome-free regions which are subsequently filled with histone H3.3, generating a surprisingly dynamic heterochromatin state. Loss of histone H3.3 elicits a highly specific opening of interstitial heterochromatin demonstrating that in the wake of Smarcad1 remodeling, H3.3 is required to maintain minimal DNA accessibility by reassembling nucleosomes.
2020-08-28 | GSE149080 | GEO
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.
2021-07-21 | PXD017300 | Pride
Project description:NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1
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Project description:WDR5 activity regulates nuclear changes and migration of acute lymphoblastic leukemia cells across confined spaces [Jurkat]
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Project description:In the ciliated protozoan Tetrahymena, de novo heterochromatin body formation is accompanied by programmed DNA elimination. Here, we show that the novel heterochromatin body component Jub1p promotes heterochromatin body formation and dephosphorylation of the Heterochromatin Protein 1 (HP1)-like protein Pdd1p. Through the identification and mutagenesis of the phosphorylated residues of Pdd1p, we demonstrate that Pdd1p dephosphorylation promotes the electrostatic interaction between Pdd1p and RNA in vitro and heterochromatin body formation in vivo. We therefore suggest that heterochromatin bodies are assembled by the Pdd1p-RNA interaction. Jub1p and Pdd1p dephosphorylation are required for heterochromatin body formation and DNA elimination but not for local heterochromatin assembly, indicating that heterochromatin body of itself plays an essential role in DNA elimination. Micronuclei (MICs) and new macronuclei (MACs) of exconjugants were isolated from different mutants at 36 hpm, and the genomic DNA was analyzed by high-throughput sequencing.
2015-12-10 | E-GEOD-70082 | 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