Genome-wide Kinase-Chromatin Interactions Reveal the Regulatory Network of ERK Signaling in Human Embryonic Stem Cells

• Published in: Molecular cell 2013-06, Vol.50 (6), p.844-855
• Main Authors: Göke, Jonathan, Chan, Yun-Shen, Yan, Junli, Vingron, Martin, Ng, Huck-Hui
• Format: Article
• Language: English
• Subjects: Base Sequence; cell cycle; Cell Differentiation; Cell Lineage; Cells, Cultured; Chromatin - enzymology; Consensus Sequence; DNA; embryonic stem cells; Embryonic Stem Cells - enzymology; Embryonic Stem Cells - physiology; ets-Domain Protein Elk-1 - genetics; ets-Domain Protein Elk-1 - metabolism; Gene Expression Regulation; Gene Knockdown Techniques; genes; Genome, Human; histones; Humans; kinases; MAP Kinase Signaling System; metabolism; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Promoter Regions, Genetic; Protein Binding; RNA, Small Interfering - genetics; RNA, Small Nuclear - genetics; RNA, Small Nuclear - metabolism; signal transduction; transcription factors; Transcription, Genetic; Transcriptome
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2013.04.030

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. [Display omitted] •Genome-wide kinase-chromatin interactions for ERK2 in hESCs•ERK2 targets noncoding, histone, cell-cycle, and metabolism genes•Motif finding and colocalization analysis reveal candidate partners of ERK2•ELK1 colocalizes with ERK2 and Polycomb and is linked to pluripotency in hESCs