Kdm5c Gene Dosage Determines Sex Differences in Adiposity
Carrie B. Wiese,1 Jenny C. Link,2 Xuqi Chen,3 Rozeta Avetisyan,1 Emilio Ronquillo,1 Feiyang Ma,4 Julia S. El-Sayed Moustafa,5 Kerrin S. Small,5 Matteo Pellegrini,4 Laurent Vergnes,1 Arthur P. Arnold,3 and Karen Reue1
1Department of Human Genetics, UCLA, 2Molecular Biology Institute, UCLA, 3Integrative Biology and Physiology, UCLA, 4Department of Molecular, Cellular and Developmental Biology, UCLA, 5Department of Twin Research and Genetic Epidemiology, King’s College London
Physiological sex differences in adipose biology and obesity have been identified between men and women. Historically, gonadal hormones have been characterized to contribute to these sex differences; however, the contribution of the sex chromosomes to these differences is not well understood. Using a mouse model that segregates sex chromosomes (XX or XY) from gonadal sex (ovaries or testes), we determined that XX chromosomal complement increased adiposity in the presence of male and female gonads. A histone demethylase encoding gene, Kdm5c, was identified to escape X inactivation and exhibit gene dosage differences in adipose depots. Importantly, Kdm5c haploinsufficient mice (Kdm5c+/–) recapitulated the adipose phenotypic differences between XX and XY mice, as the Kdm5c+/– mice had reduced body weight and fat mass compared to wildtype mice with two copies of Kdm5c. Therefore, this supports Kdm5c gene dosage levels as a determinant of the X chromosome effect on adiposity. Furthermore, modulating Kdm5c levels in 3T3-L1 preadipocytes reduced both preadipocyte proliferation and adipocyte differentiation, which corresponded to changes in chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) for genes related to extracellular matrix remodeling and cell signaling pathways. Moreover, a connection between KDM5C dosage and adiposity was identified in the TwinsUK cohort with female twins’ body mass index positively correlating with KDM5C gene expression. Collectively, we demonstrate that sex-dependent dosage of Kdm5c impacts adipocyte biology and emphasizes how sex chromosome complement and X-escape genes are critical components of physiology.
Breakout Room: Wiese, Carrie
View Poster: https://uclacns.org/symposium2021/8-Wiese-Carrie.pdf