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Gibbin (AHDC1) mesodermal regulation controls epithelial patterning

ABSTRACT: The objective of this experiment was to determine the DNA methylation status of WT and GKO hESCs treated with or without RA/BMP4.

ORGANISM(S): Homo sapiens

PROVIDER: GSE194290 | GEO | 2022/02/13

REPOSITORIES: GEO

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The Xia-Gibbs Syndrome protein Gibbin regulates mesodermal DNA methylation to pattern epithelial development (scRNA-Seq 2)

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The Xia-Gibbs Syndrome protein Gibbin regulates mesodermal DNA methylation to pattern epithelial development (ChIP-Seq)

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Gibbin mesodermal regulation patterns epithelial development.

Project description:Proper ectodermal patterning during human development requires previously identified transcription factors such as GATA3 and p63, as well as positional signalling from regional mesoderm1-6. However, the mechanism by which ectoderm and mesoderm factors act to stably pattern gene expression and lineage commitment remains unclear. Here we identify the protein Gibbin, encoded by the Xia-Gibbs AT-hook DNA-binding-motif-containing 1 (AHDC1) disease gene7-9, as a key regulator of early epithelial morphogenesis. We find that enhancer- or promoter-bound Gibbin interacts with dozens of sequence-specific zinc-finger transcription factors and methyl-CpG-binding proteins to regulate the expression of mesoderm genes. The loss of Gibbin causes an increase in DNA methylation at GATA3-dependent mesodermal genes, resulting in a loss of signalling between developing dermal and epidermal cell types. Notably, Gibbin-mutant human embryonic stem-cell-derived skin organoids lack dermal maturation, resulting in p63-expressing basal cells that possess defective keratinocyte stratification. In vivo chimeric CRISPR mouse mutants reveal a spectrum of Gibbin-dependent developmental patterning defects affecting craniofacial structure, abdominal wall closure and epidermal stratification that mirror patient phenotypes. Our results indicate that the patterning phenotypes seen in Xia-Gibbs and related syndromes derive from abnormal mesoderm maturation as a result of gene-specific DNA methylation decisions.

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Gibbin (AHDC1) mesodermal regulation controls epithelial patterning

Project description:Gibbin (AHDC1) mesodermal regulation controls epithelial patterning

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