PADI4 regulates stem cell gene expression and chromatin compaction by citrullinating histones.
Major Finding: PADI4 regulates stem cell gene expression and chromatin compaction by citrullinating histones.
Mechanism: Histone H1 citrullination reduces its nucleosomal binding and causes global chromatin decondensation.
Impact: PADI4 overexpression in tumors may lead to an open chromatin state and transcriptional deregulation.
Peptidylarginine deiminases (PADI) catalyze the posttranslational conversion of arginine to citrulline, a noncoded, uncharged amino acid, in a process known as citrullination. Christophorou and colleagues sought to determine whether PADI4-mediated citrullination, which has been implicated in cancer progression as well as chromatin decondensation in neutrophils, plays a role in pluripotency, a state that requires an open chromatin structure to maintain unrestricted differentiation capabilities. Padi4 expression, global citrullination, and histone H3 citrullination (H3cit) were detected in pluripotent mouse embryonic stem cells (ES) and induced pluripotent stem cells (iPS) but were absent in a multipotent neural stem cell line. PADI4 was found to reside within the pluripotency transcriptional network, as the pluripotency reprogramming factor OCT4 occupied the Padi4 promoter and induced Padi4 transcription. In addition, PADI4 positively regulated several genes involved in stem cell development and maintenance, such as Tcl1 and Nanog, in a manner dependent on its enzymatic activity, as chemical disruption of citrullination inhibited pluripotency gene expression. Consistent with these findings, H3cit was present on the regulatory regions of Tcl1 and Nanog in ES and iPS cells, and inhibition of PADI4 expression or catalytic activity in pre-iPS cells impaired global H3cit, reduced reprogramming efficiency, and ablated Tcl1 and Nanog expression. Furthermore, PADI4 activity was found to promote the maintenance of pluripotent cells in early mouse embryos. Unbiased proteomic analysis of mouse ES cells also identified linker histone H1 variants, which facilitate chromatin condensation, to be PADI4 targets. PADI4-induced citrullination of histone H1 arginine 54 resulted in the displacement of histone H1 from chromatin and chromatin decondensation. Taken together, these results highlight the involvement of PADI4-induced citrullination in the regulation of pluripotency-inducing factors and chromatin compaction, which suggests a possible role for upregulation of PADI4 during cancer development.
Christophorou MA, Castelo-Branco G, Halley-Stott RP, Slade Oliveira C, Loos R, Radzisheuskaya A, et al. Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature 2014 Jan 26 [Epub ahead of print].
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