ATAD2 controls chromatin-bound HIRA turnover

Abstract

Taking advantage of the evolutionary conserved nature of ATAD2, we report here a series of parallel functional studies in human, mouse, and <i>Schizosaccharomyces pombe</i> to investigate ATAD2's conserved functions. In <i>S. pombe</i>, the deletion of <i>ATAD2</i> ortholog, <i>abo1</i>, leads to a dramatic decrease in cell growth, with the appearance of suppressor clones recovering normal growth. The identification of the corresponding suppressor mutations revealed a strong genetic interaction between Abo1 and the histone chaperone HIRA. In human cancer cell lines and in mouse embryonic stem cells, we observed that the KO of <i>ATAD2</i> leads to an accumulation of HIRA. A ChIP-seq mapping of nucleosome-bound HIRA and FACT in <i>Atad2</i> KO mouse ES cells demonstrated that both chaperones are trapped on nucleosomes at the transcription start sites of active genes, resulting in the abnormal presence of a chaperone-bound nucleosome on the TSS-associated nucleosome-free regions. Overall, these data highlight an important layer of regulation of chromatin dynamics ensuring the turnover of histone-bound chaperones.