Remodeling of <i>XIST</i> regulatory landscape during primate evolution.

Abstract

Unraveling how gene regulations are remodeled during evolution is central to understanding how biological processes evolve. We explored this question in the frame of X-chromosome inactivation, a process under strong selective constraint, governed by the <i>XIST</i> lncRNA and its cis-regulators. Using functional approaches on closely related primate species, we show that <i>XIST</i> regulation has uniquely diverged over a short evolutionary timescale. In human and marmoset embryonic stem cells (ESCs), the <i>JPX</i> lncRNA gene is a major regulator of <i>XIST</i> expression. In contrast, <i>JPX</i> has a minor effect on <i>XIST</i> in macaque ESCs, where it acts together with a macaque-specific enhancer. This occurs within a reshuffled 3D organization of the <i>XIST</i> neighborhood triggered by the insertion of a HERVK transposon in the macaque lineage. Retrospective sequence comparisons revealed that many <i>XIST</i> regulators are not evolutionarily constrained, supporting the hypothesis that neutrally evolving noncoding elements harbor adaptive potential. These results illuminate how evolutionary recent elements are integrated into preexisting regulatory landscapes.