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HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE143963 | GEO | 2020/04/17

REPOSITORIES: GEO

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The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression.

Project description:Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and β-thalassemia. Previously, we discovered that silencing of the fetal γ-globin gene requires the erythroid-specific eIF2α kinase heme-regulated inhibitor (HRI), suggesting that HRI might present a pharmacologic target for raising fetal hemoglobin levels. Here, via a CRISPR-Cas9-guided loss-of-function screen in human erythroblasts, we identify transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin regulator. ATF4 directly stimulates transcription of BCL11A, a repressor of γ-globin transcription, by binding to its enhancer and fostering enhancer-promoter contacts. Notably, HRI-deficient mice display normal Bcl11a levels, suggesting species-selective regulation, which we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. Our studies uncover a linear signaling pathway from HRI to ATF4 to BCL11A to γ-globin and illustrate potential limits of murine models of globin gene regulation.

| S-EPMC7290097 | biostudies-literature

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

HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing [ChIP-seq]

2020-04-17 | GSE143961 | GEO

HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing

Project description:HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing

| PRJNA602341 | ENA

HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing [ChIP-seq]

Project description:HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing [ChIP-seq]

| PRJNA602344 | ENA

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

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

| PRJNA602343 | ENA

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A.

Project description:Reactivation of fetal hemoglobin (HbF) in adults ameliorates the severity of the common ?-globin disorders. The transcription factor BCL11A is a critical modulator of hemoglobin switching and HbF silencing, yet the molecular mechanism through which BCL11A coordinates the developmental switch is incompletely understood. Particularly, the identities of BCL11A cooperating protein complexes and their roles in HbF expression and erythroid development remain largely unknown. Here we determine the interacting partner proteins of BCL11A in erythroid cells by a proteomic screen. BCL11A is found within multiprotein complexes consisting of erythroid transcription factors, transcriptional corepressors, and chromatin-modifying enzymes. We show that the lysine-specific demethylase 1 and repressor element-1 silencing transcription factor corepressor 1 (LSD1/CoREST) histone demethylase complex interacts with BCL11A and is required for full developmental silencing of mouse embryonic ?-like globin genes and human ?-globin genes in adult erythroid cells in vivo. In addition, LSD1 is essential for normal erythroid development. Furthermore, the DNA methyltransferase 1 (DNMT1) is identified as a BCL11A-associated protein in the proteomic screen. DNMT1 is required to maintain HbF silencing in primary human adult erythroid cells. DNMT1 haploinsufficiency combined with BCL11A deficiency further enhances ?-globin expression in adult animals. Our findings provide important insights into the mechanistic roles of BCL11A in HbF silencing and clues for therapeutic targeting of BCL11A in ?-hemoglobinopathies.

| S-EPMC3631619 | biostudies-literature

Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin.

Project description:Genes encoding human ?-type globin undergo a developmental switch from embryonic to fetal to adult-type expression. Mutations in the adult form cause inherited hemoglobinopathies or globin disorders, including sickle cell disease and thalassemia. Some experimental results have suggested that these diseases could be treated by induction of fetal-type hemoglobin (HbF). However, the mechanisms that repress HbF in adults remain unclear. We found that the LRF/ZBTB7A transcription factor occupies fetal ?-globin genes and maintains the nucleosome density necessary for ?-globin gene silencing in adults, and that LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A. Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies.

| S-EPMC4778394 | biostudies-literature

Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing.

Project description:Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and β-thalassemia. BCL11A has been identified as a key regulator of HbF silencing, although its precise mechanisms of action remain incompletely understood. Recent studies have identified pathogenic mutations that cause heterozygous loss-of-function of BCL11A and result in a distinct neurodevelopmental disorder that is characterized by persistent HbF expression. While the majority of cases have deletions or null mutations causing haploinsufficiency of BCL11A, several missense variants have also been identified. Here, we perform functional studies on these variants to uncover specific liabilities for BCL11A's function in HbF silencing. We find several mutations in an N-terminal C2HC zinc finger that increase proteasomal degradation of BCL11A. We also identify a distinct C-terminal missense variant in the fifth zinc finger domain that we demonstrate causes loss-of-function through disruption of DNA binding. Our analysis of missense variants causing loss-of-function in vivo illuminates mechanisms by which BCL11A silences HbF and also suggests potential therapeutic avenues for HbF induction to treat sickle cell disease and β-thalassemia.

| S-EPMC8530301 | biostudies-literature

Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin.

Project description:The major disorders of β-globin, sickle cell disease and β-thalassemia, may be ameliorated by expression of the fetal gene paralog γ-globin. Uncertainty regarding the mechanisms repressing fetal hemoglobin in the adult stage has served as a puzzle of developmental gene regulation as well as a barrier to rational therapeutic design. Recent genome-wide association studies implicated the zinc-finger transcriptional repressor BCL11A in fetal hemoglobin regulation. Extensive genetic analyses have validated BCL11A as a potent repressor of fetal hemoglobin level. Studies of BCL11A exemplify how contextual gene regulation may often be the substrate for trait-associated common genetic variation. These discoveries have suggested novel rational approaches for the β-hemoglobin disorders including therapeutic genome editing.

| S-EPMC4705561 | biostudies-literature

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