Discovering human diabetes-risk gene function with genetics and physiological assays
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116369 | GEO | 2018/07/01
REPOSITORIES: GEO
Similar Datasets
Project description:Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdisciplinary approaches combining Drosophila genetics and physiology with human islet biology to address this fundamental gap in diabetes research. We identify Drosophila orthologs of T2D-risk genes that regulate insulin output. With human islets, we perform genetic studies and identify cognate human T2D-risk genes that regulate human beta cell function. Loss of BCL11A, a transcriptional regulator, in primary human islet cells leads to enhanced insulin secretion. Gene expression profiling reveals BCL11A-dependent regulation of multiple genes involved in insulin exocytosis. Thus, genetic and physiological systems described here advance the capacity to identify cell-specific T2D risk gene functions.
| S-EPMC6155000 | biostudies-literature
Project description:Discovering human diabetes-risk gene function with genetics and physiological assays
| PRJNA478311 | ENA
Project description:Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here we examine BCL11A as a potential regulator of HbF expression. The high HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders. BCL11A siRNA label: B, NT siRNA label: N Experiment Overall Design: Microarray expression analysis from CD34-derived erythroid progenitors treated with either non-targeting (NT) control siRNAs or BCL11A targeting siRNAs. Six samples from the NT control and six samples from the BCL11A siRNA treatment are included. Cells were harvested on day 7 of erythroid differentiation after introduction of siRNAs on day 0 of the differentiation protocol. Experiment Overall Design: 6 BCL11A siRNA datasets, 6 control (NT) datasets
2009-01-13 | E-GEOD-13284 | biostudies-arrayexpress
Project description:Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here we examine BCL11A as a potential regulator of HbF expression. The high HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders. Expression clone label: FBB (4 different subclones, with 2 arrays each), Control label: MelBirA Experiment Overall Design: Microarray expression analysis from parental control mouse erythroleukemia (MEL) cells containing the BirA enzyme (MelBirA cells) and cells containing tagged versions (FLAG-Biotag) of BCL11A. Two control datasets and eight datasets from four subclones containing tagged BCL11A are included.
2009-01-13 | E-GEOD-13283 | biostudies-arrayexpress
Project description:Basak A, Munschauer M, Lareau CA, Montbleau KE, Ulirsch JC, Hartigan CR, Schenone M, Lian J, Wang Y, Huang Y, Wu X, Gehrke L, Rice CM, An X, Christou HA, Mohandas N, Carr SA, Orkin SH, Chen JJ, Lander ES, and Sankaran VG.
Increased production of the beta-like gamma-globin genes that form fetal hemoglobin can ameliorate the severity of sickle cell disease and beta-thalassemia, the major hemoglobin disorders. BCL11A is a key repressor of the gamma-globin genes and is expressed in a developmental stage-specific manner to regulate the physiologic fetal-to-adult hemoglobin switch. Despite extensive studies, the upstream mechanisms underlying the developmental expression of BCL11A and hemoglobin switching in humans have remained mysterious. Here we show that BCL11A is regulated at the level of mRNA translation during human hematopoietic development. While BCL11A mRNA is comparably expressed at all developmental stages in erythroid cells, robust protein expression only occurs in adult erythroid cells. Importantly, at the earlier stages of development, the observed reduction in protein expression is attributable to decreased synthesis and not increased degradation of BCL11A. While BCL11A protein is not well synthesized at these earlier stages of development, its mRNA curiously continues to be associated with ribosomes. Through unbiased proteomic analyses in erythroid cells, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a reciprocal pattern to BCL11A, directly interacts with ribosomes. We show that the observed suppression of BCL11A protein translation is mediated by LIN28B through a direct interaction with BCL11A mRNA and independent of its role in let-7 microRNA biogenesis. Finally, we show that BCL11A is the major functional target in LIN28B-mediated fetal hemoglobin induction. Our results reveal a previously unappreciated regulatory mechanism underlying human hemoglobin switching and illuminate opportunities for developing improved treatments for sickle cell disease and beta-thalassemia.
2019-10-09 | MSV000084443 | MassIVE
Project description:Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here we examine BCL11A as a potential regulator of HbF expression. The high HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders. BCL11A siRNA label: B, NT siRNA label: N Keywords: cell type comparsion
2008-12-05 | GSE13284 | GEO
Project description:Genetic risk variants identified in genome-wide association studies (GWAS) of complex disease are primarily non-coding, and translating risk variants into mechanistic insight requires detailed gene regulatory maps in disease-relevant cell types. Here, we combined a GWAS of type 1 diabetes (T1D) in 520,580 samples with candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types defined using single nucleus ATAC-seq (snATAC-seq) of 131,554 nuclei. T1D risk variants were enriched in cCREs active in T cells and additional cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped exocrine-specific cCREs linked to genes with exocrine-specific expression. At the CFTR locus, T1D risk variant rs7795896 mapped in a ductal-specific cCRE which regulated CFTR, and the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of large-scale GWAS and single cell epigenomics for understanding the cellular origins of complex disease.
2021-03-15 | GSE163160 | GEO
Project description:Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here we examine BCL11A as a potential regulator of HbF expression. The high HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders. Expression clone label: FBB (4 different subclones, with 2 arrays each), Control label: MelBirA Keywords: cell type comparsion
2008-12-05 | GSE13283 | GEO
Project description:Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells. We show here that exposure to pro-inflammatory cytokines unmasks a marked plasticity of the β-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and 3D chromatin structure. Our data indicates that the β cell response to cytokines is mediated by the induction of novel regulatory regions as well as the activation of primed regulatory elements pre-bound by islet-specific transcription factors. We found that T1D-associated loci are enriched of the newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells. Our study illustrates how β cells respond to a pro-inflammatory environment and implicate a role for stimulus-response islet enhancers in T1D.
2019-09-20 | GSE137136 | GEO
Project description: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
2021-07-30 | GSE181151 | GEO