Co-regulation in embryonic stem cells via context-dependent binding of transcription factors

MOTIVATION With the accumulation of genome-wide binding data for many transcription factors (TFs) in the same cell type or cellular condition, it is of great current interest to systematically infer the complex regulatory logic among multiple TFs. In particular, ChIP-Seq data have been generated for 14 core TFs critical to the maintenance and reprogramming of mouse embryonic stem cells (ESCs). This provides a great opportunity to study the regulatory collaboration and interaction among these TFs and with other unknown co-regulators. RESULTS In combination with liquid association among gene expression profiles, we develop a computational method to predict context-dependent (CD) co-egulators of these core TFs in ESCs from pairwise binding datasets. That is, co-occupancy between a core TF and a predicted co-regulator depends on the presence or absence of binding sites of another core TF, which is regarded as a binding context. Unbiased external validation confirms that the predicted CD binding of a co-regulator is reliable. Our results reveal a detailed CD co-regulation network among the 14 core TFs and provide many other potential co-regulators showing strong agreement with the literature. AVAILABILITY See www.stat.ucla.edu/~zhou/CMF for software and source code.

[1]  Qing Zhou,et al.  Searching ChIP-seq genomic islands for combinatorial regulatory codes in mouse embryonic stem cells , 2011, BMC Genomics.

[2]  S. Orkin,et al.  An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells , 2008, Cell.

[3]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[4]  Li Chen,et al.  hmChIP: a database and web server for exploring publicly available human and mouse ChIP-seq and ChIP-chip data , 2011, Bioinform..

[5]  Stuart H. Orkin,et al.  A protein interaction network for pluripotency of embryonic stem cells , 2006, Nature.

[6]  Megan F. Cole,et al.  Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells , 2008, Cell.

[7]  A. Smith,et al.  Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. , 1998, Genes & development.

[8]  Saurabh Sinha,et al.  A Biophysical Model for Analysis of Transcription Factor Interaction and Binding Site Arrangement from Genome-Wide Binding Data , 2009, PloS one.

[9]  Yuriy L Orlov,et al.  The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. , 2010, Cell stem cell.

[10]  Stephen Dalton,et al.  Myc represses primitive endoderm differentiation in pluripotent stem cells. , 2010, Cell stem cell.

[11]  Robert Stevens,et al.  Gene Ontology Consortium , 2014 .

[12]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[13]  Leonid A. Mirny,et al.  Zfx Controls the Self-Renewal of Embryonic and Hematopoietic Stem Cells , 2007, Cell.

[14]  D. Mangelsdorf,et al.  Nuclear receptor regulation of stemness and stem cell differentiation , 2009, Experimental & Molecular Medicine.

[15]  W. Wong,et al.  A gene regulatory network in mouse embryonic stem cells , 2007, Proceedings of the National Academy of Sciences.

[16]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

[17]  Alexander E. Kel,et al.  TRANSFAC®: transcriptional regulation, from patterns to profiles , 2003, Nucleic Acids Res..

[18]  Qing Zhou,et al.  Identification of Context-Dependent Motifs by Contrasting ChIP Binding Data , 2010, Bioinform..

[19]  Radu Dobrin,et al.  Dissecting self-renewal in stem cells with RNA interference , 2006, Nature.

[20]  Christina Chaivorapol,et al.  Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells , 2007, PLoS genetics.

[21]  J. van Helden,et al.  RSAT peak-motifs: motif analysis in full-size ChIP-seq datasets , 2011, Nucleic acids research.

[22]  Mike J. Mason,et al.  Role of the Murine Reprogramming Factors in the Induction of Pluripotency , 2009, Cell.

[23]  M. Murakami,et al.  The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells , 2003, Cell.

[24]  G. Pavesi,et al.  The Short Isoform of NF‐YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry , 2012, Stem cells.

[25]  Mark Bieda,et al.  Unbiased location analysis of E2F1-binding sites suggests a widespread role for E2F1 in the human genome. , 2006, Genome research.

[26]  R. Kuick,et al.  Dax1 up-regulates Oct4 expression in mouse embryonic stem cells via LRH-1 and SRA. , 2010, Molecular endocrinology.

[27]  S. Oliviero,et al.  Myc Regulates the Transcription of the PRC2 Gene To Control the Expression of Developmental Genes in Embryonic Stem Cells , 2011, Molecular and Cellular Biology.

[28]  Timothy L. Bailey,et al.  Gene expression Advance Access publication May 4, 2011 DREME: motif discovery in transcription factor ChIP-seq data , 2011 .

[29]  F. Alt,et al.  N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation. , 2000, Genes & development.

[30]  Ker-Chau Li,et al.  Genome-wide coexpression dynamics: Theory and application , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Renato Paro,et al.  A chromatin-modifying function of JNK during stem cell differentiation , 2011, Nature Genetics.

[32]  S. Kliewer,et al.  Orphan Nuclear Receptor LRH-1 Is Required To Maintain Oct4 Expression at the Epiblast Stage of Embryonic Development , 2005, Molecular and Cellular Biology.