Gibbin mesodermal regulation patterns epithelial development

Nature. 2022 Jun;606(7912):188-196. doi: 10.1038/s41586-022-04727-9. Epub 2022 May 18.


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.

MeSH terms

  • Animals
  • DNA Methylation
  • DNA-Binding Proteins* / metabolism
  • Dermis / cytology
  • Dermis / embryology
  • Dermis / metabolism
  • Ectoderm / metabolism
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Epidermal Cells / cytology
  • Epidermal Cells / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Epithelium* / embryology
  • GATA3 Transcription Factor
  • Gene Expression Regulation, Developmental*
  • Humans
  • Mesoderm* / metabolism
  • Mice
  • Morphogenesis*
  • Mutation
  • Organoids
  • Trans-Activators
  • Transcription Factors / metabolism


  • AHDC1 protein, human
  • DNA-Binding Proteins
  • GATA3 Transcription Factor
  • Trans-Activators
  • Transcription Factors
  • Trp63 protein, mouse
  • Ahdc1 protein, mouse