Activation of Xist by an evolutionarily conserved function of KDM5C demethylase

Milan Kumar Samanta, Srimonta Gayen, Clair Harris, Emily Maclary, Yumie Murata-Nakamura, Rebecca M. Malcore, Robert S. Porter, Patricia M. Garay, Christina N. Vallianatos, Paul B. Samollow, Shigeki Iwase and Sundeep Kalantry ()
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Milan Kumar Samanta: University of Michigan Medical School
Srimonta Gayen: University of Michigan Medical School
Clair Harris: University of Michigan Medical School
Emily Maclary: University of Michigan Medical School
Yumie Murata-Nakamura: University of Michigan Medical School
Rebecca M. Malcore: University of Michigan Medical School
Robert S. Porter: University of Michigan Medical School
Patricia M. Garay: University of Michigan Medical School
Christina N. Vallianatos: University of Michigan Medical School
Paul B. Samollow: Texas A&M University
Shigeki Iwase: University of Michigan Medical School
Sundeep Kalantry: University of Michigan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract XX female and XY male therian mammals equalize X-linked gene expression through the mitotically-stable transcriptional inactivation of one of the two X chromosomes in female somatic cells. Here, we describe an essential function of the X-linked homolog of an ancestral X-Y gene pair, Kdm5c-Kdm5d, in the expression of Xist lncRNA, which is required for stable X-inactivation. Ablation of Kdm5c function in females results in a significant reduction in Xist RNA expression. Kdm5c encodes a demethylase that enhances Xist expression by converting histone H3K4me2/3 modifications into H3K4me1. Ectopic expression of mouse and human KDM5C, but not the Y-linked homolog KDM5D, induces Xist in male mouse embryonic stem cells (mESCs). Similarly, marsupial (opossum) Kdm5c but not Kdm5d also upregulates Xist in male mESCs, despite marsupials lacking Xist, suggesting that the KDM5C function that activates Xist in eutherians is strongly conserved and predates the divergence of eutherian and metatherian mammals. In support, prototherian (platypus) Kdm5c also induces Xist in male mESCs. Together, our data suggest that eutherian mammals co-opted the ancestral demethylase KDM5C during sex chromosome evolution to upregulate Xist for the female-specific induction of X-inactivation.

Date: 2022
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DOI: 10.1038/s41467-022-30352-1

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