Citrullination regulates pluripotency and histone H1 binding to chromatin
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Authors
Christophorou, Maria A
Castelo-Branco, Gonçalo
Halley-Stott, Richard P
Oliveira, Clara Slade
Loos, Remco
Radzisheuskaya, Aliaksandra
Mowen, Kerri A
Nielsen, Michael L
Publication Date
2014-01-26Journal Title
Nature
ISSN
0028-0836
Publisher
Nature Publishing Group
Volume
507
Pages
104-108
Language
English
Type
Article
Metadata
Show full item recordCitation
Christophorou, M. A., Castelo-Branco, G., Halley-Stott, R. P., Oliveira, C. S., Loos, R., Radzisheuskaya, A., Mowen, K. A., et al. (2014). Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature, 507 104-108. https://doi.org/10.1038/nature12942
Abstract
Citrullination is the post-translational conversion of an arginine residue within a protein to the non-coded amino acid citrulline [1] . This modification leads to the loss of a positive charge and reduction in hydrogen bonding ability. It is carried out by a small family of tissue-specific vertebrate enzymes called peptidylarginine deiminases (PADIs) [2] and is associated with the development of diverse pathological states such as autoimmunity, cancer, neurodegenerative disorders, prion diseases and thrombosis [2,3] . Nonetheless, the physiological functions of citrullination remain ill-defined, though citrullination of core histones has been linked to transcriptional regulation and the DNA damage response [4-8] . PADI4 (or PAD4/PADV), the only PADI with a nuclear localization signal [9] , was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune response to infection [10]. Here we show that the expression and enzymatic activity of PADI4 are also induced under conditions of ground state pluripotency and during reprogramming. PADI4 is part of the pluripotency transcriptional network, binding to regulatory elements of key stem cell genes and activating their expression. Its inhibition lowers the percentage of pluripotent cells in the early mouse embryo and significantly reduces reprogramming efficiency. Using an unbiased proteomic approach we identify linker histone H1 variants, which are involved in the generation of compact chromatin [11], as novel PADI4 substrates. Citrullination of a single arginine residue within the DNA binding site of H1 results in its displacement from chromatin and global chromatin decondensation. Together, these results uncover a role for citrullination in the regulation of pluripotency and provide new mechanistic insights into how citrullination regulates chromatin compaction.
Sponsorship
Cancer Research UK
Funder references
MRC (G1001690)
Wellcome Trust (101861/Z/13/Z)
Wellcome Trust (101050/Z/13/Z)
Wellcome Trust (092096/Z/10/Z)
Identifiers
External DOI: https://doi.org/10.1038/nature12942
This record's URL: https://www.repository.cam.ac.uk/handle/1810/254537
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