Dynamic evolution of EZHIP, an inhibitor of the Polycomb Repressive Complex 2 in mammals

The Polycomb Repressive Complex 2 (PRC2) is an ancient, conserved chromatin-interacting complex that controls gene expression, facilitating differentiation and cellular identity during development. Its regulation is critical in most eukaryotes. EZHIP was recently characterized as a PRC2 inhibitor and 'oncohistone mimic' in mammals. Although <i>Ezhip</i> expression is typically restricted to the germline, its aberrant expression in pediatric brain tumors inhibits PRC2-mediated H3K27 methylation and drives disease progression. To gain a deeper understanding of its normal functions, we systematically examined <i>Ezhip</i> evolution across 70 mammals using comparative genomics, synteny analysis, and motif discovery. Bolstering previous work, we find that <i>Ezhip</i> originated and has been strictly retained on the X chromosome in placental mammals. In addition to the highly conserved H3K27M-like histone mimic motif, our motif analysis reveals seven previously unidentified EZHIP motifs, including a putative nuclear localization signal, and tandem repeats that are largely well-conserved in placental mammals, except in some lineages. We hypothesize that these motifs are also critical to EZHIP's functions, including in PRC2 interaction and inhibition. We show that <i>Ezhip</i> has evolved under strong diversifying selection in primates and underwent dynamic expansions and losses across species. Some paralogs, such as <i>Ezhip2</i> in primates, also evolved under positive selection. Based on its evolutionary attributes and germ-cell expression, we propose that <i>Ezhip</i> arose and evolved rapidly due to inter-parental conflict over fetal development <i>in utero</i> in placental mammals. Our work provides a foundation for further investigations into EZHIP's essential, potentially multifaceted roles in mammalian reproduction and disease.