Project description:The mechanisms by which the fetal type b-globin-like genes HBG1 and HBG2 are silenced in adult erythroid precursor cells is a basic biology question in human development. Reversal of such mechanisms is beneficial for b hemoglobinopathies, such as sickle cell disease (SCD). A CRISPR-Cas9 genetic screen uncovered two members of the NFI transcription factor family – NFIA and NFIX – as novel HBG1/2 repressors. Both factors are expressed at elevated levels in adult erythroid cells, and their single or combined depletion revealed cooperativity in HBG1/2 regulation in cultured cells and human-to-mouse xenotransplant experiments, as well as in preventing sickling of SCD-derived erythroblasts. Genomic profiling, gene editing and in vitro binding assays demonstrated that the potent concerted activity of NFIA and NFIX factors is explained in part by their ability to activate expression of BCL11A, a known silencer of the HBG1/2 genes, and in part by repressing the HBG1/2 genes via two direct binding sites. NFI factors emerge as versatile regulators of the fetal-to-adult switch in b-globin production.

2022-03-23 | GSE180869 | GEO

NFI factors repress fetal hemoglobin in adult erythorid cells [CUT&RUN]

2022-03-23 | GSE180860 | GEO

NFI factors repress fetal hemoglobin in adult erythorid cells [ATAC-seq]

2022-03-23 | GSE180855 | GEO

NFI factors repress fetal hemoglobin in adult erythorid cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-03-23 | GSE180871 | GEO

Genome-wide DNA methylation differences between ex vivo differentiated cells that recapitulate the fetal-to-adult hemoglobin switch

Project description:The aim of this study is to characterize de genome-wide DNA methylation changes that occur during the fetal-to-adult hemoglobin switch in erythroblasts. We differentiated CD34+ hematopoietic progenitor cells collected for either fetal liver or bone marrow into erythroblasts. After differentiation, cells produce respectively fetal hemoglobin and adult hemoglobin in majority. We compared genome-wide DNA methylation states of fetal-stage erythroblasts to those of adult-stage erythroblasts.

2014-12-02 | GSE56491 | GEO

Chromatin Accessibility Mapping of Primary Erythroid Cell Populations Leads to Identification and Validation of NFIX As a Novel Fetal Hemoglobin Repressor

Project description:Human genetics has validated de-repression of fetal gamma globin (HBG) in adult erythroblasts as a powerful therapeutic paradigm in diseases involving defective adult beta globin (HBB)1. To identify novel factors involved in the switch from HBG to HBB expression, we performed Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq)2 on discrete sorted erythroblast populations derived from bone marrow (BM) or cord blood (CB) progenitors, representing adult and fetal states, respectively. Comparison of the ATAC-seq profiles revealed enrichment of NFI DNA binding motifs and increased chromatin accessibility at the NFIX promoter in BM populations relative to CB populations, suggesting that NFIX may repress HBG. NFIX knockdown in BM cells increased HBG mRNA and fetal hemoglobin (HbF) protein levels, coincident with increased chromatin accessibility and decreased DNA methylation at the HBG promoter. Conversely, overexpression of NFIX in CB cells reduced HbF levels. Identification of NFIX as a novel target for HbF activation has potential implications in the development of therapeutics for hemoglobinopathies.

2023-05-31 | GSE196731 | GEO

Chromatin Accessibility Mapping of Primary Erythroid Cell Populations Leads to Identification and Validation of NFIX As a Novel Fetal Hemoglobin Repressor

Project description:Human genetics has validated de-repression of fetal gamma globin (HBG) in adult erythroblasts as a powerful therapeutic paradigm in diseases involving defective adult beta globin (HBB)1. To identify factors involved in the switch from HBG to HBB expression, we performed Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq)2 on sorted erythroid lineage cells derived from bone marrow (BM) or cord blood (CB), representing adult and fetal states, respectively. BM to CB cell ATAC-seq profile comparisons revealed genome-wide enrichment of NFI DNA binding motifs and increased NFIX promoter chromatin accessibility, suggesting that NFIX may repress HBG. NFIX knockdown in BM cells increased HBG mRNA and fetal hemoglobin (HbF) protein levels, coincident with increased chromatin accessibility and decreased DNA methylation at the HBG promoter. Conversely, overexpression of NFIX in CB cells reduced HbF levels. Identification and validation of NFIX as a new target for HbF activation has implications in the development of therapeutics for hemoglobinopathies.

2023-06-07 | GSE234155 | GEO

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