Gibbin mesodermal regulation patterns epithelial development

Autor: Ann Collier, Angela Liu, Jessica Torkelson, Jillian Pattison, Sadhana Gaddam, Hanson Zhen, Tiffany Patel, Kelly McCarthy, Hana Ghanim, Anthony E. Oro
Rok vydání: 2022
Předmět:
Zdroj: Nature
ISSN: 1476-4687
0028-0836
DOI: 10.1038/s41586-022-04727-9
Popis: Proper ectodermal patterning during human development requires previously identified transcription factors such as GATA3 and p63, as well as positional signaling from regional mesoderm(1–6). However, the mechanism by which ectoderm and mesoderm factors act to stably pattern gene expression and lineage commitment remains poorly understood. Here we identify the previously unstudied protein Gibbin, encoded by the Xia-Gibbs AT-hook DNA Binding Motif Containing 1 (AHDC1) disease gene(7–9), as a key regulator of early epithelial morphogenesis. We find that enhancer/promoter-bound Gibbin interacts with dozens of sequence-specific zinc-finger transcription factors and methyl-CpG binding proteins to regulate expression of mesoderm genes. Gibbin loss causes an increase in DNA methylation at GATA3-dependent mesodermal genes, resulting in loss of signaling between developing dermal and epidermal cell types. Strikingly, Gibbin-mutant hESC-derived skin organoids lack dermal maturation, resulting in p63-expressing basal cells that possess defective keratinocyte stratification. Novel 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.
Databáze: OpenAIRE
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