Journal Article

X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity

Yao, Jie, Ronquillo, Emilio, Guo, Xiuqing, Small, Kerrin S., Vergnes, Laurent, Avetisyan, Rozeta, Chen, Yii-Der Ida, Rotter, Jerome I., El -Sayed Moustafa, Julia S., Link, Jenny C., Ma, Feiyang, Arnold, Arthur P., Wiese, Carrie B., Reue, Karen, Chen, Xuqi, Allison, Matthew, Iwase, Shigeki, Pellegrini, Matteo

2020

Overview

Males and females differ in body composition and fat distribution. Using a mouse model that segregates gonadal sex (ovaries and testes) from chromosomal sex (XX and XY), we showed that XX chromosome complement in combination with a high-fat diet led to enhanced weight gain in the presence of male or female gonads. We identified the genomic dosage of Kdm5c, an X chromosome gene that escapes X chromosome inactivation, as a determinant of the X chromosome effect on adiposity. Modulating Kdm5c gene dosage in XX female mice to levels that are normally present in males resulted in reduced body weight, fat content, and food intake to a degree similar to that seen with altering the entire X chromosome dosage. In cultured preadipocytes, the levels of KDM5C histone demethylase influenced chromatin accessibility (ATAC-Seq), gene expression (RNA-Seq), and adipocyte differentiation. Both in vitro and in vivo, Kdm5c dosage influenced gene expression involved in extracellular matrix remodeling, which is critical for adipocyte differentiation and adipose tissue expansion. In humans, adipose tissue KDM5C mRNA levels and KDM5C genetic variants were associated with body mass. These studies demonstrate that the sex-dependent dosage of Kdm5c contributes to male/female differences in adipocyte biology and highlight X-escape genes as a critical component of female physiology.

• Publisher: American Society for Clinical Investigation
• Subject: Adipocytes / Adipocytes - enzymology / Adipose tissue / Adiposity / Animals / Biomedical research / Body composition / Body fat / Body mass / Body weight / Body weight gain / Chromatin / Chromatin Assembly and Disassembly / Demographic aspects / Extracellular matrix / Female / Females / Food intake / Gender differences / Gene Dosage / Gene expression / Gene Expression Regulation, Enzymologic / Genetic aspects / Genetic diversity / Genetic research / Gonads / High fat diet / Histone Demethylases - biosynthesis / Histone Demethylases - genetics / Histones / Hormones / Humans / Male / Males / Metabolism / Mice / Mice, Mutant Strains / Ovaries / Oxidoreductases / Physiological aspects / Physiology / Preadipocytes / Sex / Sex Characteristics / Sex chromosomes / Sex differences / Sex differences (Biology) / Testes / X chromosome / X Chromosome - genetics / X Chromosome - metabolism / X chromosomes / X-chromosome inactivation / Y chromosomes