TY - JOUR
T1 - KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis
AU - Lin-Shiao, Enrique
AU - Lan, Yemin
AU - Coradin, Mariel
AU - Anderson, Amy
AU - Donahue, Greg
AU - Simpson, Cory L.
AU - Sen, Payel
AU - Saffie, Rizwan
AU - Busino, Luca
AU - Garcia, Benjamin A.
AU - Berger, Shelley L.
AU - Capell, Brian C.
N1 - Funding Information:
We are very grateful to Dr. Laura Pasqualucci for permission to use her KMT2D overexpression plasmids. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) under award number K08AR070289 to B.C.C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Further support was provided by Dermatology Foundation and Melanoma Research Foundation grants to B.C.C. as well as National Institute on Aging P01 (P01AG031862) and R01 (R01CA078831) grants to S.L.B., NIH grants GM110174 and CA196539 to B.A.G., NIH grant 1 F31 GM123744-01 to E.L.-S, and American Skin Association, Dermatology Foundation, and National Psoriasis Foundation grants to C.L.S. This research was also supported by Cores A and B of the Penn Skin Biology and Diseases Resource-based Center, funded by NIAMS 1P30AR069589-01.
Publisher Copyright:
© 2018 Lin-Shiao et al.
PY - 2018/1/15
Y1 - 2018/1/15
N2 - Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator KMT2D (MLL4) is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undiffer-entiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Genome-wide, KMT2D interacts with p63 and is enriched at its target enhancers. Depletion of KMT2D results in a broad loss of enhancer histone modifications H3 Lys 4 (H3K4) monomethylation (H3K4me1) and H3K27 acetylation (H3K27ac) as well as reduced expression of p63 target genes, including key genes involved in epithelial development and adhesion. Together, these results reveal a critical role for KMT2D in the control of epithelial enhancers and p63 target gene expression, including the requirement of KMT2D for the maintenance of epithelial progenitor gene expression and the coordination of proper terminal differentiation.
AB - Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator KMT2D (MLL4) is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undiffer-entiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Genome-wide, KMT2D interacts with p63 and is enriched at its target enhancers. Depletion of KMT2D results in a broad loss of enhancer histone modifications H3 Lys 4 (H3K4) monomethylation (H3K4me1) and H3K27 acetylation (H3K27ac) as well as reduced expression of p63 target genes, including key genes involved in epithelial development and adhesion. Together, these results reveal a critical role for KMT2D in the control of epithelial enhancers and p63 target gene expression, including the requirement of KMT2D for the maintenance of epithelial progenitor gene expression and the coordination of proper terminal differentiation.
KW - Chromatin
KW - Enhancers
KW - Epigenetics
KW - Epithelial homeostasis
KW - KMT2D
KW - P63
UR - http://www.scopus.com/inward/record.url?scp=85042189379&partnerID=8YFLogxK
U2 - 10.1101/gad.306241.117
DO - 10.1101/gad.306241.117
M3 - Article
C2 - 29440247
AN - SCOPUS:85042189379
SN - 0890-9369
VL - 32
SP - 181
EP - 193
JO - Genes and Development
JF - Genes and Development
IS - 2
ER -