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Nature. 2014 Mar 6;507(7490):104-8. doi: 10.1038/nature12942. Epub 2014 Jan 26.

Citrullination regulates pluripotency and histone H1 binding to chromatin.

Author information

1
1] The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK [2].
2
1] The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK [2] Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden [3].
3
1] The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK [2] Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK.
4
1] The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK [2] EMBRAPA Dairy Cattle Research Center, Juiz de Fora, Brazil [3] Department of Physiology, Development and Neuroscience, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
5
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK.
6
1] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK [2] Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
7
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
8
1] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK [2] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK [3] Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
9
1] The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK [2] Department of Physiology, Development and Neuroscience, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
10
Department of proteomics, The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Blegdamsvej 3b, DK-2200 Copenhagen, Denmark.
11
1] The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK [2] Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.

Abstract

Citrullination is the post-translational conversion of an arginine residue within a protein to the non-coded amino acid citrulline. 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) and is associated with the development of diverse pathological states such as autoimmunity, cancer, neurodegenerative disorders, prion diseases and thrombosis. Nevertheless, the physiological functions of citrullination remain ill-defined, although citrullination of core histones has been linked to transcriptional regulation and the DNA damage response. PADI4 (also called PAD4 or PADV), the only PADI with a nuclear localization signal, was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune response to infection. Here we show that the expression and enzymatic activity of Padi4 are also induced under conditions of ground-state pluripotency and during reprogramming in mouse. 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, 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.

PMID:
24463520
PMCID:
PMC4843970
DOI:
10.1038/nature12942
[Indexed for MEDLINE]
Free PMC Article

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