Diverse epigenetic strategies interact to control epidermal differentiation.
It is becoming clear that interconnected functional gene networks, rather than individual genes, govern stem cell self-renewal and differentiation. To identify epigenetic factors that impact on human epidermal stem cells we performed siRNA-based genetic screens for 332 chromatin modifiers. We developed a Bayesian mixture model to predict putative functional interactions between epigenetic modifiers that regulate differentiation. We discovered a network of genetic interactions involving EZH2, UHRF1 (both known to regulate epidermal self-renewal), ING5 (a MORF complex component), BPTF and SMARCA5 (NURF complex components). Genome-wide localization and global mRNA expression analysis revealed that these factors impact two distinct but functionally related gene sets, including integrin extracellular matrix receptors that mediate anchorage of epidermal stem cells to their niche. Using a competitive epidermal reconstitution assay we confirmed that ING5, BPTF, SMARCA5, EZH2 and UHRF1 control differentiation under physiological conditions. Thus, regulation of distinct gene expression programs through the interplay between diverse epigenetic strategies protects epidermal stem cells from differentiation.
Epithelial Cell Biology Group, Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, UK. klaas.mulder@cancer.org.uk
Klaas W
KW
Mulder
Xin
X
Wang
Carles
C
Escriu
Yoko
Y
Ito
Roland F
RF
Schwarz
Jesse
J
Gillis
Gábor
G
Sirokmány
Giacomo
G
Donati
Santiago
S
Uribe-Lewis
Paul
P
Pavlidis
Adele
A
Murrell
Florian
F
Markowetz
Fiona M
FM
Watt
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D001499:Bayes Theorem; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D000078404:Epidermal Cells; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008957:Models, Genetic; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D055153:Stem Cell Niche / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000092468:Bromodomain Containing Proteins
D000251:Adenosine Triphosphatases; D034961:Antigens, Nuclear; D022762:CCAAT-Enhancer-Binding Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D016023:Integrins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D063151:Polycomb Repressive Complex 2; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C508131:ING5 protein, human; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins; C498409:EZH2 protein, human; C406364:UHRF1 protein, human; C409462:SMARCA5 protein, human