Methylation of RNA polymerase II non-consensus Lysine residues marks early transcription in mammalian cells

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Abstract

Dynamic post-translational modification of RNA polymerase II (RNAPII) coordinates the co-transcriptional recruitment of enzymatic complexes that regulate chromatin states and processing of nascent RNA. Extensive phosphorylation of serine residues at the largest RNAPII subunit occurs at its structurally-disordered C-terminal domain (CTD), which is composed of multiple heptapeptide repeats with consensus sequence Y₁-S₂-P₃-T₄-S₅-P₆-S₇. Serine-5 and Serine-7 phosphorylation mark transcription initiation, whereas Serine-2 phosphorylation coincides with productive elongation. In vertebrates, the CTD has eight non-canonical substitutions of Serine-7 into Lysine-7, which can be acetylated (K7ac). Here, we describe mono- and di-methylation of CTD Lysine-7 residues (K7me1 and K7me2). K7me1 and K7me2 are observed during the earliest transcription stages and precede or accompany Serine-5 and Serine-7 phosphorylation. In contrast, K7ac is associated with RNAPII elongation, Serine-2 phosphorylation and mRNA expression. We identify an unexpected balance between RNAPII K7 methylation and acetylation at gene promoters, which fine-tunes gene expression levels.

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João D Dias

Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Tiago Rito

Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Elena Torlai Triglia

Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Alexander Kukalev

Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Carmelo Ferrai

Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Mita Chotalia

Genome Function Group, MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Emily Brookes

MRC Laboratory for Molecular and Cell Biology, University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Hiroshi Kimura

Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan

Competing interests
The authors declare that no competing interests exist.
Ana Pombo

Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin, Germany

For correspondence
ana.pombo@mdc-berlin.de

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All handling of mice was approved by the Hokkaido University Animal Experiment Committee (approval number: 11-0109) and carried out according to guidelines for animal experimentation at Hokkaido University, where MAB Institute Inc. is located. Animals were housed in a designated pathogen-free facility at Hokkaido University. Mice were humanely euthanized via cervical dislocation by technically proficient individuals.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.