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HEXIM1 Overexpression Alters GATA1 Activity and Promotes Fetal Globin Expression

ABSTRACT: HEXIM1 Overexpression Alters GATA1 Activity and Promotes Fetal Globin Expression

PROVIDER: PRJNA879767 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21536603_1.fastq.gz	Fastqsanger.gz
	SRR21536603_2.fastq.gz	Fastqsanger.gz
	SRR21536604_1.fastq.gz	Fastqsanger.gz
	SRR21536604_2.fastq.gz	Fastqsanger.gz
	SRR21536605_1.fastq.gz	Fastqsanger.gz

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HEXIM1 Overexpression Alters GATA1 Activity and Promotes Fetal Globin Expression

Project description:Erythropoiesis is a highly organized process whereby multipotent HSCs become committed to the erythroid linage and mature into enucleate erythrocytes. Recent work from our lab demonstrated that HEXIM1 is essential in the regulation of erythroid proliferation, viability and gene expression, and also promotes the expression of GATA1 target genes. New analyses of HEXIM1 overexpression (OE) in HUDEP2 cells revealed a significant increase of gamma globin production, with a higher proportion of cells expressing fetal hemoglobin. To gain insights into the mechanisms underlying the increased fetal globin expression, we performed CUT&RUN assays for Ser5 phosphorylated and total RNPII in HEXIM1 OE and control cells. Surprisingly, OE of HEXIM1 had only modest impacts on RNPII pausing, but instead lead to changes in the genes occupied by RNPII. Our results support a model where elevated HEXIM1 levels promote the pioneer activity of GATA1, and facilitate the expression of a fetal transcriptional program in adult cells in a pTEFb-dependent manner.

2023-11-30 | GSE213220 | GEO

Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin

Project description:Naturally occurring mutations in the Î³-globin promoters can result in hereditary persistence of fetal hemoglobin (HPFH), a benign condition that ameliorates the severity of Î²-hemoglobinopathies through increased post-natal fetal hemoglobin (HbF) expression. Mutations in the Î³-globin promoters result in loss or de novo recruitment of transcription factors, yet the cis-regulatory elements involved in Î³-globin transcription in the context of HPFH are not clearly defined. We demonstrate that the -115 cluster of HPFH mutations require GATA1 binding to at -186 in cooperation with NF-Y at the proximal CCAAT box at -85 for Î³-globin expression. We show that multiple HPFH mutations increase HbF in an erythroid cell line and result in GATA1 binding at -186. Mutation of the -186 GATA motif in HPFH erythroid cell lines and erythroid-differentiated CD34+ cells resulted in loss of GATA1 binding and reduction in fetal hemoglobin. NF-Y ChIP-seq in HPFH erythroid cell lines demonstrated binding to the proximal CCAAT box at -85 was also found to be critical for HPFH-mediated Î³-globin expression. Together, the -186 GATA motif and -85 proximal CCAAT box function in an additive and independent manner. Our results reveal detailed evidence for common, positive acting cis-regulatory elements that may provide more general mechanisms for erythroid gene expression.

2021-04-22 | GSE152338 | GEO

The pivotal and universal role of BGLT3 lncRNA in fetal globin gene expression

Project description:A highly selective and non-genotoxic G9a inhibitor, RK-701 was discovered, which upregulated the mRNA level of γ-globin but not β-globin both in human erythroid cells and in mice. Using RK-701, we examined the induction of the fetal (γ-) globin protein in human erythroid cells; HUDEP-2 and human CD34+ bone marrow and peripheral blood cells.

2023-03-11 | PXD033536 | Pride

Recombinant erythroid Kruppel-like factor fused to GATA1 up-regulates delta- and gamma-globin expression in erythroid cells primary adult human erythroid progenitor cells

Project description:The EKLF-GATA1 fusion proteins enhances δ-globin expression through interaction with the GATA1-binding motif of the δ-globin promoter. The goal this study is to find if the fusion proteins could have a different pattern of chromatin occupation from GATA1. The alignment of ChIP-Seq peaks revealed that the binding peaks of EKLF-GATA1 fusion proteins at the β-globin cluster overlapped substantially with those of GATA1 (A), suggesting that these proteins may associate with chromatin in a similar configuration within the β-globin locus and LCR. Global analysis of EKLF-GATA1 and GATA1 ChIP-seq data sets also revealed a significant number of shared sites on the genomic scale.

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Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin

Project description:Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin

| PRJNA639052 | ENA

Natural regulatory mutations elevate fetal globin via disruption of BCL11A or ZBTB7A binding

Project description:B-hemoglobinopathies such as Sickle Cell Disease (SCD) and b-thalassemia result from mutations in the adult b-globin gene. Reactivating the developmentally silenced fetal g-globin gene is a therapeutic goal for treating SCD and b-thalassemia1. Some forms of Hereditary Persistence of Fetal Hemoglobin (HPFH), a rare benign condition in which individuals express g‑globin throughout adulthood, are caused by point mutations in the g‑globin gene promoter at regions residing ~115 and 200 base pairs upstream of the transcription start site. Here we show that the major fetal globin repressors BCL11A and ZBTB7A/LRF directly bind to the -115 and ‑200 sites, respectively. Furthermore, introduction of naturally occurring HPFH mutations into erythroid cells by CRISPR/Cas9 disrupts repressor binding and raises g‑globin expression. These findings resolve the mystery surrounding how these HPFH mutations operate and demonstrate that BCL11A and ZBTB7A/LRF are major direct repressors of the fetal globin gene.

2018-01-29 | GSE103445 | GEO

Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies

Project description:We have identified putative repressor region (PRR) to exon-1 of β-globin (βE1) in the β-globin cluster as a core region in alll the HPFH deletions that activates fetal hemoglobin and silences adult hemoglobin. Here we charactised the transcriptome of the erythroblasts derived from PRR-βE1 gene edited HSPCs. Transcriptome analysis showed an increased expression of HBG, HBBP1 and decreased expression of HBB transcripts compared to control.

2022-04-25 | GSE201346 | GEO

Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies [4C]

Project description:We have identified putative repressor region (PRR) to exon-1 of β-globin (βE1) in the β-globin cluster as a core region in alll the HPFH deletions that activates fetal hemoglobin and silences adult hemoglobin. To test the impact of PRR-βE1 gene editing in β-globin cluster configuration, we employed Circular chromosome conformation capture (4C) analysis to assess the LCR interaction to the gamma-globin promoter. Using HBG2 promoter as viewpoint,4C analysis showed an increased interaction of HBG promoter to the hypersensitive (HS) sites of the LCR in HUDEP-2 clones harbouring PRR-βE1 biallelic deletions compared to control HUDEP-2 cells. Link for 4C output files Mendeley - Venkatesan, Vigneshwaran (2022), “4C data set ”, Mendeley Data, V1, doi: 10.17632/cz3thnr9kf.1

2022-04-26 | GSE201388 | GEO

Heme and GATA1 coordinately regulate erythroid differentiation [expression]

Project description:In mice lacking the heme exporter, FLVCR, differentiation fails at the CFU-E/proerythroblast stage from excessive heme and reactive oxygen species. We show that Flvcr1-deleted CFU-E/proerythroblasts have low GATA1 mRNA and GATA1-target gene mRNAs along with increased ribosomal protein mRNAs as a direct result of increased heme. Thus heme increases ribosomal protein transcription when globin production needs to be increased, and when heme is excessive, GATA1 is reduced allowing for normal termination of erythroid differentiation. This demonstrates that heme and GATA1 are co-master regulators of erythroid differentiation.

2019-02-07 | GSE94905 | GEO

KLF1 directly activates expression of the novel fetal globin repressor, ZBTB7A/LRF, in erythroid cells

Project description:Genes encoding the human β-like hemoglobin proteins undergo a developmental switch from fetal γ-globin to adult β-globin expression at around the time of birth. β-hemoglobinopathies, such as sickle cell disease and β-thalassemia, result from mutations affecting the adult β-globin gene. The only treatment options currently available carry significant side-effects. Analyses of heritable variations in fetal hemoglobin (HbF) levels have provided evidence that reactivation of the silenced fetal γ-globin genes in adult erythroid cells is a promising therapy. The γ-globin repressor BCL11A has become the major focus with several studies investigating its regulation and function as a first step to inhibiting its expression or activity. However, a second repression mechanism has recently been shown to be mediated by the transcription factor ZBTB7A/LRF, suggesting that understanding the regulation of ZBTB7A may also be useful. Here we show that KLF1 directly drives expression of ZBTB7A in erythroid cells by binding to its proximal promoter. We have also uncovered an erythroid-specific regulation mechanism, leading to the upregulation of a novel ZBTB7A transcript in the erythroid compartment. The demonstration that ZBTB7A, like BCL11A, is a KLF1 target gene also fits with the observation that reduced KLF1 expression or activity is associated with HbF derepression.

2017-04-13 | GSE97671 | GEO

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