Diverse epigenetic strategies interact to control epidermal differentiation

Klaas W. Mulder; Xin Wang; Carles Escriu; Yoko Ito; Roland F. Schwarz; Jesse Gillis; Gábor Sirokmány; Giacomo Donati; Santiago Uribe-Lewis; Paul Pavlidis; Adele Murrell; Florian Markowetz; Fiona M. Watt

doi:10.1038/ncb2520

Diverse epigenetic strategies interact to control epidermal differentiation

Klaas W. Mulder, Xin Wang, Carles Escriu, Yoko Ito, Roland F. Schwarz, Jesse Gillis, Gábor Sirokmány, Giacomo Donati, Santiago Uribe-Lewis, Paul Pavlidis, Adele Murrell, Florian Markowetz, Fiona M. Watt

Research output: Contribution to journal › Article › peer-review

121 Citations (SciVal)

Abstract

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.

Original language	English
Pages (from-to)	753-763
Number of pages	11
Journal	Nature cell biology
Volume	14
Issue number	7
Early online date	24 Jun 2012
DOIs	https://doi.org/10.1038/ncb2520
Publication status	Published - 1 Jul 2012

Bibliographical note

Funding Information:
We thank A. Brenkman, J. Carroll, N. Rosenfeld, M. Narita, D. Odom and Watt laboratory members for critical discussion and comments. This work was supported by Cancer Research UK (CRUK), Hutchinson Wampoa, University of Cambridge (F.M.W.) and a Marie Curie Fellowship (PIEF-GA-2008-220642) to K.W.M. We are indebted to the core facilities of the CRUK Cambridge Research Institute for excellent technical assistance.

Keywords

Adenosine Triphosphatases
Antigens, Nuclear
Bayes Theorem
CCAAT-Enhancer-Binding Proteins
Cell Adhesion
Cell Differentiation
Cells, Cultured
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone
Cluster Analysis
DNA-Binding Proteins
Epidermis
Epigenesis, Genetic
Gene Expression Regulation
Gene Regulatory Networks
Humans
Integrins
Keratinocytes
Models, Genetic
Multiprotein Complexes
Nerve Tissue Proteins
Polycomb Repressive Complex 2
RNA Interference
RNA, Messenger
Stem Cell Niche
Stem Cells
Transcription Factors
Transfection
Tumor Suppressor Proteins

ASJC Scopus subject areas

Cell Biology

Access to Document

10.1038/ncb2520

Cite this

@article{e985588f918c4b8293af22156ccf58f5,

title = "Diverse epigenetic strategies interact to control epidermal differentiation",

abstract = "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.",

keywords = "Adenosine Triphosphatases, Antigens, Nuclear, Bayes Theorem, CCAAT-Enhancer-Binding Proteins, Cell Adhesion, Cell Differentiation, Cells, Cultured, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, Cluster Analysis, DNA-Binding Proteins, Epidermis, Epigenesis, Genetic, Gene Expression Regulation, Gene Regulatory Networks, Humans, Integrins, Keratinocytes, Models, Genetic, Multiprotein Complexes, Nerve Tissue Proteins, Polycomb Repressive Complex 2, RNA Interference, RNA, Messenger, Stem Cell Niche, Stem Cells, Transcription Factors, Transfection, Tumor Suppressor Proteins",

author = "Mulder, {Klaas W.} and Xin Wang and Carles Escriu and Yoko Ito and Schwarz, {Roland F.} and Jesse Gillis and G{\'a}bor Sirokm{\'a}ny and Giacomo Donati and Santiago Uribe-Lewis and Paul Pavlidis and Adele Murrell and Florian Markowetz and Watt, {Fiona M.}",

note = "Funding Information: We thank A. Brenkman, J. Carroll, N. Rosenfeld, M. Narita, D. Odom and Watt laboratory members for critical discussion and comments. This work was supported by Cancer Research UK (CRUK), Hutchinson Wampoa, University of Cambridge (F.M.W.) and a Marie Curie Fellowship (PIEF-GA-2008-220642) to K.W.M. We are indebted to the core facilities of the CRUK Cambridge Research Institute for excellent technical assistance.",

year = "2012",

month = jul,

day = "1",

doi = "10.1038/ncb2520",

language = "English",

volume = "14",

pages = "753--763",

journal = "Nature cell biology",

issn = "1476-4679",

publisher = "Nature Research",

number = "7",

}

TY - JOUR

T1 - Diverse epigenetic strategies interact to control epidermal differentiation

AU - Mulder, Klaas W.

AU - Wang, Xin

AU - Escriu, Carles

AU - Ito, Yoko

AU - Schwarz, Roland F.

AU - Gillis, Jesse

AU - Sirokmány, Gábor

AU - Donati, Giacomo

AU - Uribe-Lewis, Santiago

AU - Pavlidis, Paul

AU - Murrell, Adele

AU - Markowetz, Florian

AU - Watt, Fiona M.

N1 - Funding Information: We thank A. Brenkman, J. Carroll, N. Rosenfeld, M. Narita, D. Odom and Watt laboratory members for critical discussion and comments. This work was supported by Cancer Research UK (CRUK), Hutchinson Wampoa, University of Cambridge (F.M.W.) and a Marie Curie Fellowship (PIEF-GA-2008-220642) to K.W.M. We are indebted to the core facilities of the CRUK Cambridge Research Institute for excellent technical assistance.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - 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.

AB - 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.

KW - Adenosine Triphosphatases

KW - Antigens, Nuclear

KW - Bayes Theorem

KW - CCAAT-Enhancer-Binding Proteins

KW - Cell Adhesion

KW - Cell Differentiation

KW - Cells, Cultured

KW - Chromatin Assembly and Disassembly

KW - Chromosomal Proteins, Non-Histone

KW - Cluster Analysis

KW - DNA-Binding Proteins

KW - Epidermis

KW - Epigenesis, Genetic

KW - Gene Expression Regulation

KW - Gene Regulatory Networks

KW - Humans

KW - Integrins

KW - Keratinocytes

KW - Models, Genetic

KW - Multiprotein Complexes

KW - Nerve Tissue Proteins

KW - Polycomb Repressive Complex 2

KW - RNA Interference

KW - RNA, Messenger

KW - Stem Cell Niche

KW - Stem Cells

KW - Transcription Factors

KW - Transfection

KW - Tumor Suppressor Proteins

UR - http://www.scopus.com/inward/record.url?scp=84863222901&partnerID=8YFLogxK

U2 - 10.1038/ncb2520

DO - 10.1038/ncb2520

M3 - Article

C2 - 22729083

SN - 1476-4679

VL - 14

SP - 753

EP - 763

JO - Nature cell biology

JF - Nature cell biology

IS - 7

ER -

Diverse epigenetic strategies interact to control epidermal differentiation

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this