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X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity
- Source :
- J Clin Invest
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
X Chromosome
Gene Dosage
Adipose tissue
Gene Expression Regulation, Enzymologic
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Adipocyte
Internal medicine
Gene expression
medicine
Adipocytes
Animals
Humans
Gene
X chromosome
Adiposity
Histone Demethylases
Sex Characteristics
biology
Chromosome
General Medicine
Chromatin Assembly and Disassembly
Mice, Mutant Strains
030104 developmental biology
Endocrinology
Histone
chemistry
030220 oncology & carcinogenesis
biology.protein
Demethylase
Female
Research Article
Subjects
Details
- ISSN :
- 15588238
- Volume :
- 130
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation
- Accession number :
- edsair.doi.dedup.....e69b494032b527409eb7f3d8792dcf0b