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Open Access Highly Accessed Research article

Potential role for PADI-mediated histone citrullination in preimplantation development

Rui Kan1, Mei Jin1, Venkataraman Subramanian2, Corey P Causey3, Paul R Thompson2 and Scott A Coonrod1*

Author Affiliations

1 Baker Institute for Animal Health, Cornell University, Ithaca, NY, 14850, USA

2 Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA

3 Department of Chemistry, University of North Florida, Jacksonville, FL, 32224, USA

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BMC Developmental Biology 2012, 12:19  doi:10.1186/1471-213X-12-19

Published: 19 June 2012

Abstract

Background

The peptidylarginine deiminases (PADIs) convert positively charged arginine residues to neutrally charged citrulline on protein substrates in a process that is known as citrullination or deimination. Previous reports have documented roles for histone citrullination in chromatin remodeling and gene regulation in several tissue types, however, a potential role for histone citrullination in chromatin-based activities during early embryogenesis has not been investigated.

Results

In the present study, we tested by laser scanning confocal indirect immunofluorescence microscopy whether specific arginine residues on the histone H3 and H4 N-terminal tails (H4R3, H3R2 + 8 + 17, and H3R26) were citrullinated in mouse oocytes and preimplantation embryos. Results showed that all of the tested residues were deiminated with each site showing a unique localization pattern during early development. Given these findings, we next tested whether inhibition of PADI activity using the PADI-specific inhibitor, Cl-amidine, may affect embryonic development. We found that treatment of pronuclear stage zygotes with Cl-amidine reduces both histone H3 and H4 tail citrullination and also potently blocks early cleavage divisions in vitro. Additionally, we found that the Cl-amidine treatment reduces acetylation at histone H3K9, H3K18, and H4K5 while having no apparent effect on the repressive histone H3K9 dimethylation modification. Lastly, we found that treatment of zygotes with trichostatin A (TSA) to induce hyperacetylation also resulted in an increase in histone citrullination at H3R2 + 8 + 17.

Conclusions

Given the observed effects of Cl-amidine on embryonic development and the well documented correlation between histone acetylation and transcriptional activation, our findings suggest that histone citrullination may play an important role in facilitating gene expression in early embryos by creating a chromatin environment that is permissive for histone acetylation.

Keywords:
Peptidylarginine deiminase; Citrullination; Histone modification; Preimplantation development; Cl-amidine