title: Genome-wide kinase-chromatin interactions reveal the regulatory network of ERK signaling in human embryonic stem cells.
abstract: The extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase signal-transduction cascade is one of the key pathways regulating proliferation and differentiation in development and disease. ERK signaling is required for human embryonic stem cells' (hESCs') self-renewing property. Here, we studied the convergence of the ERK signaling cascade at the DNA by mapping genome-wide kinase-chromatin interactions for ERK2 in hESCs. We observed that ERK2 binding occurs near noncoding genes and histone, cell-cycle, metabolism, and pluripotency-associated genes. We find that the transcription factor ELK1 is essential in hESCs and that ERK2 co-occupies promoters bound by ELK1. Strikingly, promoters bound by ELK1 without ERK2 are occupied by Polycomb group proteins that repress genes involved in lineage commitment. In summary, we propose a model wherein extracellular-signaling-stimulated proliferation and intrinsic repression of differentiation are integrated to maintain the identity of hESCs.
authors.affiliation: Gene Regulation Laboratory, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Göke
authors.forename: Yun-Shen
authors.initials: YS
authors.lastname: Chan
authors.forename: Junli
authors.initials: J
authors.lastname: Yan
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.forename: Huck-Hui
authors.initials: HH
authors.lastname: Ng
mesh_terms: D001483:Base Sequence; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D002843:Chromatin / Q000201:enzymology*; D016384:Consensus Sequence; D053595:Embryonic Stem Cells / Q000201:enzymology* / Q000502:physiology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D015894:Genome, Human; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D012342:RNA, Small Nuclear / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; C494112:ELK1 protein, human; D063146:Polycomb-Group Proteins; D034741:RNA, Small Interfering; D012342:RNA, Small Nuclear; D050807:ets-Domain Protein Elk-1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1