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

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

PROVIDER: PRJNA639052 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12002867_1.fastq.gz	Fastqsanger.gz
	SRR12002867_2.fastq.gz	Fastqsanger.gz
	SRR12002868_1.fastq.gz	Fastqsanger.gz
	SRR12002868_2.fastq.gz	Fastqsanger.gz
	SRR12002869_1.fastq.gz	Fastqsanger.gz

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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

microRNA expression profiles of reticulocytes for hereditary persistence of fetal hemoglobin and β-thalssemia minor with high fetal hemoglobin.

Project description:We used microarrays to investigate differential microRNA (miRNA) expression in reticulocytes comparing reticulocytes from control individuals with normal fetal hemoglobin (HbF) level to hereditary persistence of fetal hemoglobin (HPFH) and β-thalssemia minor with high HbF, and try to find out some miRNAs associated with the mechanisms of HbF induction.

2018-01-01 | GSE93973 | GEO

The long noncoding RNA expression profiles of reticulocytes for hereditary persistence of fetal hemoglobin and β-thalssemia minor with high fetal hemoglobin.

Project description:To explore long noncoding RNA (lncRNA) expression and the biological functions of lncRNAs in fetal hemoglobin (HbF) induction, we surveyed lncRNA and mRNA expression profiles using circulating reticulocytes isolated from individuals with hereditary persistence of fetal hemoglobin (HPFH) and β-thalassaemia minor with high HbF.

2018-01-01 | GSE93971 | GEO

Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch

Project description:Fetal hemoglobin (HbF) level is genetically controlled and modifies severity of adult hemoglobin (HbA) disorders. Common genetic variation affects expression of BCL11A, a critical regulator of HbF silencing. Current models suggest that BCL11A acts at a distance from the gamma-globin genes via long-distance chromosomal interactions. Here we use a functional cellular assay and protein-binding microarray to establish a requirement for a zinc-finger cluster of BCL11A for globin repression, and identify a preferred DNA recognition sequence (TGACCA). The motif is present in embryonic and fetal-expressed globin promoters, and duplicated in gamma-globin promoters, yet only the distal motif is mutated in alleles of individuals with hereditary persistence of hemoglobin. Using CUT&RUN to map protein binding sites, we detected BCL11A occupancy preferentially at the distal motif, and validated its absence in HbF-expressing, promoter-edited erythroid cells. Taken together, our findings reveal that direct gamma-globin gene promoter repression by BCL11A underlies hemoglobin switching.

2018-03-30 | GSE104676 | GEO

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:Hereditary persistence of fetal hemoglobin (HPFH) ameliorates β-hemoglobinopathies by inhibiting the developmental switch from γ-globin (HBG1/HBG2) to β-globin (HBB) gene expression. Some forms of HPFH are associated with γ-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain γ-globin gene expression postnatally remains undefined. We mapped γ-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce γ-globin expression by facilitating the recruitment of nuclear transcription factor Y (NF-Y) to a nearby proximal CCAAT box and GATA1 to an upstream motif. The proximal CCAAT element becomes dispensable for HPFH variants that generate new binding motifs for activators NF-Y or KLF1, but GATA1 recruitment remains essential. Our findings define distinct mechanisms through which transcription factors and their cis-regulatory elements activate γ-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing.

| S-EPMC8610173 | biostudies-literature

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

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.

2021-11-21 | GSE189272 | GEO

Micro-Capture-C to determine the long-range interaction of HBG1/2 promoter with the locus control region (LCR), a powerful upstream enhancer in -175 A>G mutantant HUDEP-2 cells.

Project description:Naturally occurring mutations in the γ-globin promoters can result in hereditary persistence of fetal hemoglobin (HPFH), a benign condition that ameliorates the severity of β-hemoglobinopathies through increased post-natal fetal hemoglobin (HbF) expression. Base editing to recreate the HPFH mutations is a promising approach to induce HbF. Compared with Cas9-generated indels, base-editing approaches were more potent, with the −175 A>G conversion resulting in the strongest induction of HbF by creating a new TAL1 binding motif that stimulates long-range interaction with the locus control region (LCR), a powerful upstream enhancer. Micro-Capture-C analysis showed that introducing the −175 A>G variant stimulated long-range interaction between the γ-globin promoters and the LCR in erythroid progenitor cell line. Together, these findings show that the −175 A>G variant creates a bipartite GATA–TAL1 motif, resulting in the assembly of a GATA1/TAL1/LMO2/LDB1 complex, which activates γ-globin gene transcription by enhancing its physical association with the LCR.

2023-04-28 | GSE228570 | GEO

Transcription factor competition at the γ-globin promoters controls hemoglobin switching [ATACseq]

Project description:BCL11A, the major regulator of HbF(α2γ2) level, represses γ-globin expression through direct promoter binding in adult erythroid cells in a switch to adult adult-type HbA (α2β2) production. Yet, the mechanism remains unclear. To uncover how BCL11A initiates repression, we used CRISPR/Cas9 and dCas9 screens to dissect the γ-globin promoters and identified an apparent activator element near the BCL11A binding region. Using CUT&RUN and base editing approaches, we demonstrate that this element, the proximal CCAAT box, is the binding site of transcription activator NF-Y. BCL11A competes with NF-Y binding through steric hindrance to initiate γ-globin repression, and the distance between the two motifs is critical for direct competition. Occupancy of NF-Y is rapidly established upon BCL11A depletion, and precedes γ-globin derepression and LCR-globin loop formation. Our findings reveal that the critical fetal-to-adult hemoglobin switch is initiated by the competition between transcription factors within a discrete region in the γ-globin promoters.

2020-12-22 | GSE150488 | GEO

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