Peptidylarginine deiminase 1-catalyzed histone citrullination is essential for early embryo development

Abstract

Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullination. As one of the PADI family members, PADI1 has been mainly reported to be expressed in the epidermis and uterus, where the protein in keratinocytes is thought to promote differentiation by citrullinating filament proteins. However, the roles of PADI1 in preimplantation development have not been addressed. Using a PADI1-specific inhibitor and Padi1-morpholino knockdown, we found that citrullination of histone tails at H4R3 and H3R2/8/17 were markedly reduced in the 2- and 4-cell embryos. Consistent with this observation, early embryo development was also arrested at the 4-cell stage upon depletion of PADI1 or inhibition of PADI1 enzyme activity. Additionally, by employing 5-ethynyl uridine (EU) incorporation analysis, ablation of PADI1 function led to a dramatic decrease in overall transcriptional activity, correlating well with the reduced levels of phosphorylation of RNA Pol II at Ser2 observed at 2- or 4-cell stage of embryos under Padi1 knockdown or inhibiting PADI1. Thus, our data reveal a novel function of PADI1 during early embryo development transitions by catalyzing histone tail citrullination, which facilitates early embryo genome transactivation.

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

“…PADIs catalyzed histone citrullination also controls transcription regulation and chromatin organization [47][48][49][50][51][52][53][54][55][56]. Remarkably, citrullinated histones found to account for approximately 10% of all histone molecules, emphasizing the essential role of this posttranslational modification in many physiological processes in the nucleus [48].…”

“…For example, during preimplantation and early-stage embryo development histone citrullination can lead to chromatin changes [49]. Specifically, PADI1 citrullinates both the histone H3 at 2, 8 and 17 positions (H3Cit2, 8, 17) and histone H4 at arginine 3 (H4Cit3) during 2-and 4-cell stage embryo development, which facilitates early embryo genome transactivation [50]. However, the potential implications of PADI1-directed histone citrullination had not been investigated yet.…”

Mechanisms and Inhibitors of Histone Arginine Methylation

“…[78] On the other hand, dimethylated H3R2 is reported to be a site for demethylation by Jumonji domain containing 6 protein (JMJD6), and H3R2 is a potential site for deimination by peptidylarginine deiminase 1 (PADI1) to produce citrulline. [79] Hence, while we have highlighted major crosstalk events between arginine methylation and other histone PTMs, there is a larger picture to appreciate.…”

Citrullination regulates wound responses and tissue regeneration in zebrafish

“…1 G), indicating that Padi2 is likely the PAD that mediates citrullination activity at 2 dpf. Although previous studies have indicated that mammalian PAD1 and PADI6 are necessary for normal development (Esposito et al, 2007; Kan et al, 2012; Zhang et al, 2016), we found that the Padi2-deficient zebrafish did not display any gross morphological defects and had normal viability (Fig. S2, A and B).…”