HIC2 regulates maturation of the cardiovascular system
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE100125 | GEO | 2017/06/17
SECONDARY ACCESSION(S): PRJNA390764
REPOSITORIES: GEO
Similar Datasets
Project description:Rationale: 22q11 deletion syndrome arises from recombination between low copy repeats on chromosome 22. Typical deletions result in hemizygosity for TBX1 associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack extra-cardiac features of the syndrome suggesting that a second haploinsufficient gene maps to this interval. Objective: The transcription factor HIC2 is lost in most distal deletions as well as a minority of typical deletions. We used mouse models to test the hypothesis that HIC2 hemizygosity causes congenital heart disease. Methods and Results: We created a genetrap mouse allele of Hic2. The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5 while the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. Magnetic resonance imaging demonstrated a ventricular septal defect with overriding aorta. Conditional targeting indicated a requirement for Hic2 within the Nkx2.5+ and Mesp1+ cardiovascular progenitor lineages but not in the Wnt1+ neural crest or Mef2c+ second heart field lineages. Microarray analysis revealed increased expression of BMP10. Conclusions: Our results demonstrate a novel role for Hic2 in cardiac development. Hic2 is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggests HIC2 haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome. The aim of this microarray experiment was to compare gene expression changes in the E13.5 mouse heart in a conditional knockout of Hic2 (Mesp1Cre/+; Hic2FL/FL) against control. All samples represent pools of isolated hearts from E13.5 mouse embryos. 3 replicates of each genotype were assayed. The genotypes are: 'WT' (Hic2FL/FL) 'KO' (Mesp1Cre/+; Hic2 FL/FL)
2014-04-02 | E-GEOD-56430 | biostudies-arrayexpress
Project description:Rationale: 22q11 deletion syndrome arises from recombination between low copy repeats on chromosome 22. Typical deletions result in hemizygosity for TBX1 associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack extra-cardiac features of the syndrome suggesting that a second haploinsufficient gene maps to this interval. Objective: The transcription factor HIC2 is lost in most distal deletions as well as a minority of typical deletions. We used mouse models to test the hypothesis that HIC2 hemizygosity causes congenital heart disease. Methods and Results: We created a genetrap mouse allele of Hic2. The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5 while the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. Magnetic resonance imaging demonstrated a ventricular septal defect with overriding aorta. Conditional targeting indicated a requirement for Hic2 within the Nkx2.5+ and Mesp1+ cardiovascular progenitor lineages but not in the Wnt1+ neural crest or Mef2c+ second heart field lineages. Microarray analysis revealed increased expression of BMP10. Conclusions: Our results demonstrate a novel role for Hic2 in cardiac development. Hic2 is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggests HIC2 haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome. the aim of this microarray experiment was to compare gene expression changes in the E13.5 mouse heart in a conditional knockout of Hic2 (Mesp1Cre/+; Hic2FL/FL) against control.
2014-04-02 | GSE56430 | GEO
Project description:Mouse embryonic fibroblasts (MEFs) with doxycycline (Dox)-inducible reprogramming cassette MKOS-ires-mOrange and a Nanog-GFP reporter were transduced with lentiviral Dox-inducible Ty1-BFP (blue fluoresce protein with Ty1 tag in the N-terminus) or Hic2-Ty1 (Hic2 with Ty1 tag in the C-terminus) expression vector with MOI 5. One day later reprogramming was initiated by the administration of Dox. 48 hours later, the cells for Hic2 ChIP-seq with anti-Ty1 antibody were crosslinked with 2mM of Disuccinimidyl Glutarate (DSG) for 45 min at room temperature (RT) under constant agitation, before being cross-linked with 1% formaldehyde solution for 10 min at room temperature. For KLF4 ChIP-seq, cells were only cross-linked with 1% formaldehyde solution for 10 min at room temperature. ChIP-seq library was generated with the NEBNext Ultra-II DNA Library Prep kit. Each library was uniquely barcoded using NEBNext Multiplex Oligos for Illumina. Samples were sequenced with the NextSeq High 40PE.
2024-04-26 | E-MTAB-13170 | biostudies-arrayexpress
Project description:The fetal hemoglobin (HBG) regulator BCL11A is repressed by HIC2 to regulate hemoglobin switching. HIC2 itself is under developmental control, highly expressed in fetal tissues and decreased in adult cells, but the mechanism of this developmental regulation is unclear. Here, we demonstrate that HIC2 is developmentally controlled by miRNAs, and loss of global miRNA biogenesis through DICER1 depletion leads to upregulation of HIC2 and HBG. We subsequently identify the adult-expressed let-7 miRNA family as a repressor of HIC2 expression. Ectopic expression of let-7 in fetal-type cells repressed HIC2 levels, while let-7 inhibition in adult erythroblasts upregulated HIC2 levels. Let-7 regulates BCL11A and HBG through induction of HIC2 and reduction of GATA1 binding at the BCL11A erythroid enhancer. Finally, HIC2 depletion rescues BCL11A-mediated repression of fetal hemoglobin in let-7 inhibited cells. Together these data demonstrate a key miRNA-mediated mechanism for developmental regulation of BCL11A expression and fetal hemoglobin repression in adult erythroid cells.
2024-02-05 | GSE216196 | GEO
Project description:The fetal hemoglobin (HBG) regulator BCL11A is repressed by HIC2 to regulate hemoglobin switching. HIC2 itself is under developmental control, highly expressed in fetal tissues and decreased in adult cells, but the mechanism of this developmental regulation is unclear. Here, we demonstrate that HIC2 is developmentally controlled by miRNAs, and loss of global miRNA biogenesis through DICER1 depletion leads to upregulation of HIC2 and HBG. We subsequently identify the adult-expressed let-7 miRNA family as a repressor of HIC2 expression. Ectopic expression of let-7 in fetal-type cells repressed HIC2 levels, while let-7 inhibition in adult erythroblasts upregulated HIC2 levels. Let-7 regulates BCL11A and HBG through induction of HIC2 and reduction of GATA1 binding at the BCL11A erythroid enhancer. Finally, HIC2 depletion rescues BCL11A-mediated repression of fetal hemoglobin in let-7 inhibited cells. Together these data demonstrate a key miRNA-mediated mechanism for developmental regulation of BCL11A expression and fetal hemoglobin repression in adult erythroid cells.
2024-02-05 | GSE216195 | GEO
Project description:The fetal hemoglobin (HBG) regulator BCL11A is repressed by HIC2 to regulate hemoglobin switching. HIC2 itself is under developmental control, highly expressed in fetal tissues and decreased in adult cells, but the mechanism of this developmental regulation is unclear. Here, we demonstrate that HIC2 is developmentally controlled by miRNAs, and loss of global miRNA biogenesis through DICER1 depletion leads to upregulation of HIC2 and HBG. We subsequently identify the adult-expressed let-7 miRNA family as a repressor of HIC2 expression. Ectopic expression of let-7 in fetal-type cells repressed HIC2 levels, while let-7 inhibition in adult erythroblasts upregulated HIC2 levels. Let-7 regulates BCL11A and HBG through induction of HIC2 and reduction of GATA1 binding at the BCL11A erythroid enhancer. Finally, HIC2 depletion rescues BCL11A-mediated repression of fetal hemoglobin in let-7 inhibited cells. Together these data demonstrate a key miRNA-mediated mechanism for developmental regulation of BCL11A expression and fetal hemoglobin repression in adult erythroid cells.
2024-02-05 | GSE216194 | GEO
Project description:The fetal hemoglobin (HBG) regulator BCL11A is repressed by HIC2 to regulate hemoglobin switching. HIC2 itself is under developmental control, highly expressed in fetal tissues and decreased in adult cells, but the mechanism of this developmental regulation is unclear. Here, we demonstrate that HIC2 is developmentally controlled by miRNAs, and loss of global miRNA biogenesis through DICER1 depletion leads to upregulation of HIC2 and HBG. We subsequently identify the adult-expressed let-7 miRNA family as a repressor of HIC2 expression. Ectopic expression of let-7 in fetal-type cells repressed HIC2 levels, while let-7 inhibition in adult erythroblasts upregulated HIC2 levels. Let-7 regulates BCL11A and HBG through induction of HIC2 and reduction of GATA1 binding at the BCL11A erythroid enhancer. Finally, HIC2 depletion rescues BCL11A-mediated repression of fetal hemoglobin in let-7 inhibited cells. Together these data demonstrate a key miRNA-mediated mechanism for developmental regulation of BCL11A expression and fetal hemoglobin repression in adult erythroid cells.
2024-02-05 | GSE216190 | GEO
Project description:The switch from fetal to adult hemoglobin production has been studied in great depth in part because of its relevance to the treatment of hemolobinopathies. Transcription factor BCL11A, which is essential for repression of the fetal beta-type globin (γ-globin) genes after birth, is largely controlled at the level of transcription but the mechanism of BCL11A developmental control is unknown. Here, using a CRISPR-Cas9 screen in human erythroblasts, we identify transcription factor HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A expression are anti-correlated in fetal and adult erythroblasts. Forced expression of HIC2 in adult erythroblasts silences BCL11A transcription and markedly induces γ-globin expression. HIC2 binds selectively to constituent erythroid developmental BCL11A enhancer to reduce chromatin accessibility and impair access by transcription factor GATA1, resulting in loss of enhancer activity and enhancer-promoter contacts. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, enables GATA1 binding and induces BCL11A transcription. HIC2 is unveiled as a critical evolutionarily conserved regulator of globin gene switching by imposing developmental control on the BCL11A gene.
2022-05-26 | GSE173586 | GEO
Project description:The switch from fetal to adult hemoglobin production has been studied in great depth in part because of its relevance to the treatment of hemolobinopathies. Transcription factor BCL11A, which is essential for repression of the fetal beta-type globin (γ-globin) genes after birth, is largely controlled at the level of transcription but the mechanism of BCL11A developmental control is unknown. Here, using a CRISPR-Cas9 screen in human erythroblasts, we identify transcription factor HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A expression are anti-correlated in fetal and adult erythroblasts. Forced expression of HIC2 in adult erythroblasts silences BCL11A transcription and markedly induces γ-globin expression. HIC2 binds selectively to constituent erythroid developmental BCL11A enhancer to reduce chromatin accessibility and impair access by transcription factor GATA1, resulting in loss of enhancer activity and enhancer-promoter contacts. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, enables GATA1 binding and induces BCL11A transcription. HIC2 is unveiled as a critical evolutionarily conserved regulator of globin gene switching by imposing developmental control on the BCL11A gene.
2022-05-26 | GSE173583 | GEO
Project description:The switch from fetal to adult hemoglobin production has been studied in great depth in part because of its relevance to the treatment of hemolobinopathies. Transcription factor BCL11A, which is essential for repression of the fetal beta-type globin (γ-globin) genes after birth, is largely controlled at the level of transcription but the mechanism of BCL11A developmental control is unknown. Here, using a CRISPR-Cas9 screen in human erythroblasts, we identify transcription factor HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A expression are anti-correlated in fetal and adult erythroblasts. Forced expression of HIC2 in adult erythroblasts silences BCL11A transcription and markedly induces γ-globin expression. HIC2 binds selectively to constituent erythroid developmental BCL11A enhancer to reduce chromatin accessibility and impair access by transcription factor GATA1, resulting in loss of enhancer activity and enhancer-promoter contacts. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, enables GATA1 binding and induces BCL11A transcription. HIC2 is unveiled as a critical evolutionarily conserved regulator of globin gene switching by imposing developmental control on the BCL11A gene.
2022-05-26 | GSE173582 | GEO