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Activation of Xist by an evolutionarily conserved function of KDM5C demethylase

Samanta, MK and Gayen, S and Harris, C and Maclary, E and Murata-Nakamura, Y and Malcore, RM and Porter, RS and Garay, PM and Vallianatos, CN and Samollow, PB and Iwase, S and Kalantry, S (2022) Activation of Xist by an evolutionarily conserved function of KDM5C demethylase. In: Nature Communications, 13 (1).

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Official URL: https://doi.org/10.1038/s41467-022-30352-1


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.

Item Type: Journal Article
Publication: Nature Communications
Publisher: Nature Research
Additional Information: The copyright for this article belongs to the Authors.
Keywords: cell; chromosome; enzyme; gene expression; mammal, long untranslated RNA, animal; female; genetics; male; mammal; marsupial; metabolism; mouse; platypus (mammal); X chromosomal inheritance; X chromosome; X chromosome inactivation, Animals; Female; Genes, X-Linked; Male; Mammals; Marsupialia; Mice; Platypus; RNA, Long Noncoding; X Chromosome; X Chromosome Inactivation
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited: 17 Sep 2022 03:22
Last Modified: 17 Sep 2022 03:22
URI: https://eprints.iisc.ac.in/id/eprint/76574

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