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Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
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MK3 controls Polycomb target gene expression via negative feedback on ERK.

Peggy Prickaerts1,2, Hanneke Ec Niessen1, Emmanuèle Mouchel-Vielh2

  • 1Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.

Epigenetics & Chromatin
|August 9, 2012
PubMed
Summary

Mitogen-activated protein kinases (MAPKs) regulate gene transcription via Polycomb repressive complex 1 (PRC1) by controlling its chromatin association. This study reveals MK3

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Area of Science:

  • Epigenetics and Gene Regulation
  • Molecular Biology
  • Cellular Signaling Pathways

Background:

  • Gene-environment interactions are mediated by epigenetic mechanisms, involving Polycomb Group proteins in transcriptional memory.
  • Understanding the dynamic chromatin association of Polycomb repressive complexes (PRCs) during development is limited.
  • MK3 interacts with Polycomb repressive complex 1 (PRC1), but its functional relevance is poorly understood.

Purpose of the Study:

  • To investigate how MK3 and its effector kinases (MAPK/ERK, SAPK/P38) regulate PRC1-dependent transcription of the ATF3 gene.
  • To elucidate the molecular mechanisms controlling PRC1's dynamic chromatin association and dissociation.

Main Methods:

  • Studied the immediate-early response gene ATF3 as a model for PRC1-dependent transcription.
  • Utilized cell culture and molecular signaling pathway analysis (ERK, P38, MK3).
  • Investigated histone modifications (H3S28 phosphorylation, H3K27me3) and protein-chromatin interactions (BMI1, pERK).

Main Results:

  • Mitogenic signaling via ERK, P38, and MK3 regulates ATF3 expression through PRC1/chromatin dissociation and epigenetic modulation.
  • ERK signaling drives PRC1 dissociation from chromatin, while P38-dependent H3S28 phosphorylation is insufficient alone.
  • pERK is a novel signaling-induced binding partner of PRC1; MK3 provides negative feedback on M/SAPKs, supported by Drosophila studies.

Conclusions:

  • Identified key components of a PRC1-dependent epigenetic signal/response mechanism with modular specificity.
  • Provided novel insight into Polycomb-mediated epigenetic control of gene transcription.
  • Established a direct link between PRC1 and cellular responses to microenvironmental changes.