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Removable insulator facilitates higher-order chromatin remodeling and selective gene expression in the HOXA locus via the retinoic acid signaling [ChIP-seq]

ABSTRACT: Chromatin insulators partition the genome into the functional units to control gene expression especially in complex chromosomal regions. The CCCTC-binding factor (CTCF) is an insulator-binding protein which functions for transcriptional regulation and higher-order chromatin formation. Here we report that a removable CTCF insulator is responsible for the retinoic acid (RA)-mediated higher-order chromatin remodeling and selective gene expression in the human HOXA gene locus. Our detailed chromatin analyses characterized multiple CTCF-enriched sites and RA-responsive enhancers in this locus. These regulatory elements and transcriptionally silent HOXA genes were closely positioned under the basal condition. Notably, upon the RA signaling, the transcription factor RAR/RXR induced the loss of an adjacent CTCF binding and changed the higher-order chromatin conformation of the overall locus, establishing transcriptionally active, poised and repressive domains that were separated by stably localizing CTCF insulators. This study uncovers that removable insulator spatiotemporally switches higher-order chromatin and multiple gene activities at the chromosomal domain levels, via the cooperation of CTCF and key transcription factors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80705 | GEO | 2017/01/10

SECONDARY ACCESSION(S): PRJNA319760

REPOSITORIES: GEO

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Removable insulator facilitates higher-order chromatin remodeling and selective gene expression in the HOXA locus via the retinoic acid signaling [ChIP-chip]

Project description:Chromatin insulators partition the genome into the functional units to control gene expression especially in complex chromosomal regions. The CCCTC-binding factor (CTCF) is an insulator-binding protein which functions for transcriptional regulation and higher-order chromatin formation. Here we report that a removable CTCF insulator is responsible for the retinoic acid (RA)-mediated higher-order chromatin remodeling and selective gene expression in the human HOXA gene locus. Our detailed chromatin analyses characterized multiple CTCF-enriched sites and RA-responsive enhancers in this locus. These regulatory elements and transcriptionally silent HOXA genes were closely positioned under the basal condition. Notably, upon the RA signaling, the transcription factor RAR/RXR induced the loss of an adjacent CTCF binding and changed the higher-order chromatin conformation of the overall locus, establishing transcriptionally active, poised and repressive domains that were separated by stably localizing CTCF insulators. This study uncovers that removable insulator spatiotemporally switches higher-order chromatin and multiple gene activities at the chromosomal domain levels, via the cooperation of CTCF and key transcription factors.

2017-01-10 | GSE65930 | GEO

Removable insulator facilitates higher-order chromatin remodeling and selective gene expression in the HOXA locus via the retinoic acid signaling

Project description:Removable insulator facilitates higher-order chromatin remodeling and selective gene expression in the HOXA locus via the retinoic acid signaling

| PRJNA319758 | ENA

Homo sapiens

Project description:Removable insulator facilitates higher-order chromatin remodeling and selective gene expression in the HOXA locus via the retinoic acid signaling [ChIP-seq]

| PRJNA319760 | ENA

Homo sapiens

Project description:Removable insulator facilitates higher-order chromatin remodeling and selective gene expression in the HOXA locus via the retinoic acid signaling [ChIP-chip]

| PRJNA275432 | ENA

Altered topology drives oncogenic programs in SDH-deficient GIST

Project description:<p>Metabolic lesions with pleiotropic effects on epigenetic regulation and other cellular processes are widely implicated in cancer, yet their oncogenic mechanisms remain poorly understood. Succinate dehydrogenase (SDH) deficiency causes a subset of gastrointestinal stromal tumors (GISTs) with DNA hyper-methylation. Here we associate this hyper-methylation with changes in chromosome topology that activate oncogenic programs. To investigate epigenetic alterations in this disease, we systematically mapped DNA methylation, CTCF insulators, enhancers and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes share similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on disrupted insulators that partitions super-enhancers from FGF3, FGF4 and the KIT oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancers and oncogenes. CRISPR-mediated excision of the corresponding CTCF motif in an SDH-intact model disrupted the boundary and up-regulated FGFs and KIT expression. Our findings reveal how a metabolic lesion destabilizes chromatin structure to facilitate the initiation and selection of epigenetic alterations that drive oncogenic programs in the absence of canonical mutations.</p>

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RNAi-independent role for Argonaute2 in CTCF/CP190 chromatin insulator function

Project description:Chromatin insulators and Polycomb group (PcG) complexes control nuclear organization to effect changes in gene expression. In Drosophila, RNA silencing pathways influence long range interactions mediated by PcG proteins and nuclear localization of the gypsy insulator; however, the underlying mechanisms are unknown. Here, we identify a singular requirement for Argonaute2 (AGO2) for the activity of the CCCTC-binding factor (CTCF)/Centrosomal protein 190 (CP190) dependent Fab-8 insulator. AGO2 and CP190 interact physically, and genome wide localization of AGO2 by chromatin immunoprecipitation and sequencing (ChIP-seq) reveals extensive colocalization of AGO2 with insulators and Polycomb Response Elements (PREs) but minimal overlap with regions of endogenous small interfering RNA (endo-siRNA) production. Finally, depletion of either CTCF or CP190 results in loss of AGO2 association with insulators, PREs, and other cis-regulatory regions. Our findings suggest that Dicer-independent recruitment of AGO2 to chromatin by insulator proteins promotes the definition of transcriptional domains throughout the genome. ChIP-seq of AGO2 in two Drosophila cell types (S2 and S3)

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CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [Hi-C and PLAC-seq]

Project description:Insulators play a critical role in spatiotemporal gene expression in metazoans by separating active and repressive chromatin domains and preventing inappropriate enhancer-promoter contacts. The evolutionarily conserved CCCTC-binding factor (CTCF) is required for insulator function in mammals, but not all of its binding sites act as insulators. Here, we explore the sequence requirements of CTCF-mediated transcriptional insulation with the use of a sensitive insulator reporter assay in mouse embryonic stem cells. We find that potent insulation is provided by multiple CTCF binding sites. Furthermore, CTCF-mediated insulation is dependent on DNA sequences adjacent to its core binding motifs, and CTCF binding sites from topologically associating domains (TAD) boundaries are more likely to function as insulators than those outside TAD boundaries independent of binding strength. Using chromosomal conformation capture assays and high resolution chromatin imaging techniques, we demonstrate that insulators reduce enhancer-promoter contacts by forming local chromatin domains. Taken together, our results provide strong genetic, molecular and imaging evidence connecting chromatin topology to action of insulators in the mammalian genome.

2020-07-06 | GSE153402 | GEO

CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [ChIP-seq]

2020-07-06 | GSE153400 | GEO

CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [RNA-seq]

2020-11-25 | GSE162101 | GEO

A CTCF binding element regulates RA-induced early ESCs differentiation through orchestrating long-range chromatin interactions between its adjacent enhancers and HoxA

Project description:Proper Homeobox A (HoxA) cluster genes expression is essential for embryonic stem cells (ESCs) differentiation and individual development. However, the mechanisms controlling the precise spatiotemporal expression of HoxA cluster genes during early ESCs differentiation remain largely unknown. Here, we find a CTCF binding element (CBE+47kb) closest to the 3'-end of HoxA locus within a topologically associated domains (TAD) in ESCs. CRISPR-Cas9 mediated the CBE+47kb knockout significantly promotes expression of HoxA cluster genes and early ESCs differentiation induced by RA compared with wild type cells. In mechanism, we found that there was a significant differently long-range chromatin interactions between its adjacent enhancers and HoxA in CBE+47kb knockout cells through chromosome conformation capture assay (Capture-C), indicating that CBE+47kb can precisely organize interactions between its adjacent enhancers and HoxA chromatins. Furthermore, we also showed that its adjacent enhancers deletion shows significantly synthetic inhibition effect on HoxA genes expression, suggesting that these enhancers are required for RA-induced HoxA genes expression. Our study reveals that a new functional CBE+47 can regulate HoxA genes expression through orchestrating long-range chromatin interactions between its adjacent enhancers and HoxA, thus maintaining RA-induced early ESCs proper differentiation.

2020-07-16 | GSE154495 | GEO

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