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Analysis of locus-specific long-range chromatin interactions in BCL11A WT and KO HUDEP-2 cells by CAPTURE

ABSTRACT: We determined the locus-specific long-range chromatin interactions associated with the human beta-globin gene cluster in BCL11A wild-type and knockout HUDEP-2 cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE181151 | GEO | 2021/07/30

REPOSITORIES: GEO

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Analysis of locus-specific long-range chromatin interactions in BCL11A WT and KO HUDEP-2 cells by CAPTURE

Project description:Analysis of locus-specific long-range chromatin interactions in BCL11A WT and KO HUDEP-2 cells by CAPTURE

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HIC2 represses BCL11A transcription to regulate hemoglobin switching during development (Capture-C)

Project description:The switch from fetal to adult hemoglobin production has been studied in great depth in part because of its relevance to the treatment of hemolobinopathies. Transcription factor BCL11A, which is essential for repression of the fetal beta-type globin (γ-globin) genes after birth, is largely controlled at the level of transcription but the mechanism of BCL11A developmental control is unknown. Here, using a CRISPR-Cas9 screen in human erythroblasts, we identify transcription factor HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A expression are anti-correlated in fetal and adult erythroblasts. Forced expression of HIC2 in adult erythroblasts silences BCL11A transcription and markedly induces γ-globin expression. HIC2 binds selectively to constituent erythroid developmental BCL11A enhancer to reduce chromatin accessibility and impair access by transcription factor GATA1, resulting in loss of enhancer activity and enhancer-promoter contacts. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, enables GATA1 binding and induces BCL11A transcription. HIC2 is unveiled as a critical evolutionarily conserved regulator of globin gene switching by imposing developmental control on the BCL11A gene.

2022-05-26 | GSE173583 | GEO

HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing [Capture-C]

Project description:Through a CRISPR-Cas9 guided loss-of-function screen in human erythroid cells we identified transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin repressor. ATF4 binds to a BCL11A enhancer to augment promoter contacts, stimulates BCL11A transcription to repress γ-globin expression. Notably, mice deficient for HRI displayed normal Bcl11a levels, suggesting species selective regulation that we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. This illustrates potential limits of commonly used murine models of globin gene regulation.

2020-04-17 | GSE143962 | GEO

Reactivation of Zeta-Globin by deletion of BCL11A and LRF in HUDEP cells

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The glucocorticoid receptor elicited proliferative response in human erythropoiesis is BCL11A-dependent

Project description:Prior evidence indicates that the erythroid cellular response to glucocorticoids (GC) has developmental specificity, namely, that developmentally more advanced cells that are undergoing or have undergone fetal to adult globin switching are more responsive to GC-induced expansion. To investigate the molecular underpinnings of this, we focused on the major developmental globin regulator BCL11A. We compared: a) levels of expression and nuclear content of BCL11A in adult erythroid cells upon GC stimulation; b) response to GC of CD34+ cells from patients with BCL11A microdeletions and reduced BCL11A expression, and; c) response to GC of two cellular models (HUDEP-2 and adult CD34+ cells) before and after reduction of BCL11A expression by shRNA. We observed that: a) GC-expanded erythroid cells from a large cohort of blood donors displayed amplified expression and nuclear accumulation of BCL11A; b) CD34+ cells from BCL11A microdeletion patients generated fewer erythroid cells when cultured with GC compared to their parents, while the erythroid expansion of the patients was similar to that of their parents in cultures without GC, and; c) adult CD34+ cells and HUDEP-2 cells with shRNA-depleted expression of BCL11A exhibit reduced expansion in response to GC. In addition, RNA-seq profiling of shRNA-BCL11A CD34+ cells cultured with and without GC was similar (very few differentially expressed genes), while GC-specific responses (differential expression of GILZ and of numerous additional genes) were observed only in controls cells with unperturbed BCL11A expression. These data indicate that BCL11A is an important participant of certain aspects of the stress pathway sustained by GC.

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The glucocorticoid receptor elicited proliferative response in human erythropoiesis is BCL11A-dependent, microdeletion patients.

2024-09-01 | GSE275337 | GEO

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Reactivation of Zeta-Globin by deletion of BCL11A and LRF in HUDEP cells (ChIP-seq)

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Expression data from BCL11A-null and wild-type bone marrow erythroid pregenitors

Project description:BCL11A is a critical mediator of hemoglobin switching and gamma-globin silencing. In this study, we showed the BCL11A is required in vivo for developmental silencing of gamma-globin genes in adult animals. We used microarray to determine the changes in gene expression profile after loss of BCL11A in adult erythroid cells CD71+Ter119+ erythroid progenitor cells were FACS-sorted from bone marrows of 6-week old control (Bcl11a +/+) and BCL11A knockout (Bcl11a fl/fl EpoR-Cre+) mice.

2012-03-22 | E-GEOD-28333 | biostudies-arrayexpress

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells

Project description:Reactivation of fetal hemoglobin expression by down-regulation of BCL11A is a promising treatment of -hemoglobinopathies. A detailed understanding of BCL11A-mediated repression of -globin gene (HBG1/2) transcription is lacking, as studies to date used perturbations by shRNA or CRISPR/Cas9 gene editing. We leveraged the dTAG PROTAC platform to acutely deplete BCL11A protein in erythroid cells and examined consequences by PRO-seq, proteomics, chromatin accessibility, and histone profiling. Among ≤ 31 genes repressed by BCL11A, HBG1/2 and HBZ show the most abundant and progressive changes in transcription and chromatin accessibility upon BCL11A loss. Transcriptional changes at HBG1/2 were detected in < 2h. Robust HBG1/2 reactivation upon acute BCL11A-depletion occurred without loss of promoter 5methylcytosine (5mC). Using targeted protein degradation, we establish a hierarchy of gene reactivation at BCL11A targets, in which nascent transcription is followed by increased chromatin accessibility, and both are uncoupled from promoter DNA methylation at the HBG1/2 loci.

2023-10-24 | PXD030307 | Pride

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