Editors' ChoiceEpigenetics

ERK Poises RNA Pol II

Sci. Signal.  04 Mar 2014:
Vol. 7, Issue 315, pp. ec63
DOI: 10.1126/scisignal.2005229

In undifferentiated embryonic stem cells (ESCs), the promoters of many developmental lineage-specification genes exist in a “poised” transcriptional state indicated by the presence of a “bivalent” chromatin mark [histone H3 trimethylated on Lys4 and Lys27 (H3K27me3)] and Ser5-phosphorylated RNA polymerase II (RNAPII). Whereas the transcription factor II H (TFIIH) kinase complex generally phosphorylates Ser5 of RNAPII bound to transcriptionally active genes, Tee et al. found that ERK2 (extracellular signal–regulated kinase 2) phosphorylates Ser5 of RNAPII on poised genes. In murine ESCs exposed to an inhibitor of MEKs, kinases that activate ERKs or those with a genetic deficiency for ERK1 and ERK2, the promoters of developmental genes showed reduced H3K27me3 and decreased association with proteins of the polycomb repressive complex (PRC2), which catalyzes H3K27me3. These effects were reversed by overexpression of ERK2 in ERK-deficient ESCs. ESCs in which ERKs were inhibited maintained expression of pluripotency genes and repression of developmental genes, suggesting that they remained in an undifferentiated state. Genome-wide chromatin immunoprecipitation analyses revealed that ERK2 bound to the promoters of developmental genes at sites that overlapped with those bound by a PRC2 protein but not a component of the TFIIH complex. Sequence analysis and mobility shift assays showed that ERK2 bound directly to DNA to a motif similar to that bound by PRC2 proteins. ERK-deficient ESCs and ESCs exposed to the MEK inhibitor, but not a TFIIH inhibitor, showed reduced association of RNAPII phosphorylated at Ser5 with the promoters of developmental genes. ERK2 phosphorylated Ser5 of RNAPII in vitro and coimmunoprecipitated with RNAPII from lysates of ESCs. Overexpression of ERK2, but not a kinase dead mutant of ERK2, in ERK-deficient cells partially restored the association of RNAPII phosphorylated at Ser5 with the promoters of developmental genes. Experimentally induced differentiation of ESCs reduced the binding of ERK2 to the promoters of development genes. Thus, ERK2 is a DNA-binding RNAPII-directed kinase that acts to keep development genes in a poised transcriptional state in undifferentiated ESCs.

W.-W. Tee, S.S. Shen, O. Oksuz, V. Narendra, D. Reinberg, Erk1/2 activity promotes chromatin features and RNAPII phosphorylation at developmental promoters in mouse ESCs. Cell 156, 678–690 (2014). [PubMed]

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