Gibbin mesodermal regulation patterns epithelial development

Ann Collier, Angela Liu, Jessica Torkelson, Jillian Pattison, Sadhana Gaddam, Hanson Zhen, Tiffany Patel, Kelly McCarthy, Hana Ghanim and Anthony E. Oro ()
Additional contact information
Ann Collier: Stanford University
Angela Liu: Stanford University
Jessica Torkelson: Stanford University
Jillian Pattison: Stanford University
Sadhana Gaddam: Stanford University
Hanson Zhen: Stanford University
Tiffany Patel: Stanford University
Kelly McCarthy: Stanford University
Hana Ghanim: Stanford University
Anthony E. Oro: Stanford University

Nature, 2022, vol. 606, issue 7912, 188-196

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-04727-9

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