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KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis

Enrique Lin-Shiao1,2, Yemin Lan1, Mariel Coradin1

  • 1Penn Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Genes & Development
|February 15, 2018
PubMed

Insights

The epigenetic regulator KMT2D is crucial for maintaining epithelial tissue balance. Its depletion disrupts cell proliferation, differentiation, and epidermal development by affecting p63 target gene expression.

Area of Science:

  • Cell Biology
  • Epigenetics
  • Developmental Biology

Background:

  • Epithelial tissues require precise regulation of self-renewal, proliferation, and differentiation for normal function.
  • Disruptions in these processes are linked to carcinogenesis.
  • The epigenetic regulator KMT2D (MLL4) is frequently mutated in cancers, but its role in normal epithelial tissues is unclear.

Purpose of the Study:

  • To investigate the function of KMT2D in maintaining the balance of epithelial tissue homeostasis.
  • To elucidate the molecular mechanisms by which KMT2D regulates epithelial cell behavior.

Main Methods:

  • Depletion of KMT2D in undifferentiated epidermal keratinocytes.
  • Genome-wide analysis of KMT2D interactions with transcription factors (p63).
  • Assessed enhancer activity via histone modifications (H3K4me1, H3K27ac) and gene expression analysis.

Main Results:

  • KMT2D depletion led to reduced keratinocyte proliferation and premature terminal differentiation.
  • KMT2D was found to interact with p63 and localize to its target enhancers.
  • Loss of KMT2D resulted in decreased enhancer marks and reduced expression of p63 target genes essential for epithelial development and adhesion.

Conclusions:

  • KMT2D plays a critical role in controlling epithelial enhancers and p63 target gene expression.
  • KMT2D is required for maintaining epithelial progenitor gene expression.
  • KMT2D is essential for coordinating proper terminal differentiation in epithelial tissues.
Keywords:
KMT2Dchromatinenhancersepigeneticsepithelial homeostasisp63

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