Remodeling of XIST regulatory landscape during primate evolution

Area of Science:

• Evolutionary biology
• Genetics
• Molecular biology

Background:

• X-chromosome inactivation is crucial for mammalian development and gene dosage.
• The XIST lncRNA and its cis-regulators govern this process.
• Understanding the evolution of gene regulation is key to understanding biological evolution.

Purpose of the Study:

• To investigate the evolutionary remodeling of gene regulation in X-chromosome inactivation.
• To explore the divergence of XIST regulation across primate species.

Main Methods:

• Functional assays in human, marmoset, and macaque embryonic stem cells (ESCs).
• Analysis of XIST lncRNA regulation by JPX lncRNA and enhancers.
• Investigation of 3D genome organization and transposon insertions.
• Retrospective sequence comparisons of XIST regulators.

Main Results:

• XIST regulation diverged rapidly across closely related primate species.
• JPX is a major XIST regulator in human and marmoset ESCs, but not macaques.
• A macaque-specific enhancer and HERVK transposon insertion reshaped XIST regulation in macaques.
• Many XIST regulators show lack of evolutionary constraint, suggesting neutral evolution potential.

Conclusions:

• Recent evolutionary elements can integrate into existing regulatory landscapes.
• Noncoding elements evolving neutrally may harbor adaptive potential.
• XIST regulation provides a model for rapid evolutionary divergence of gene regulation.