The impact of chromosomal sex on cardiometabolic health and disease

• Published in: Trends in endocrinology and metabolism 2023-10, Vol.34 (10), p.652-665
• Main Authors: Wiese, Carrie B., Avetisyan, Rozeta, Reue, Karen
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Animals; Atherosclerosis; Autoimmune Diseases; Disease Models, Animal; Epigenomics; Female; four core genotypes mouse model; gene regulation; gonadal sex; Male; Mice; sex chromosomes; X chromosome inactivation escape
• ISSN: 1043-2760; 1879-3061; 1879-3061
• DOI: 10.1016/j.tem.2023.07.003

Both sex chromosomes and gonadal hormones influence cellular metabolism to generate sex biases in cardiometabolic traits.Males and females exhibit widespread differences in gene expression across the autosomes as well as the sex chromosomes.Sex biases exist at several levels of gene regulation including epigenetic modifications and pre- and post-translational processes.X chromosome dosage has direct effects on gene expression levels through enhanced expression of specific genes that escape X chromosome inactivation.Genes that escape X chromosome inactivation include histone demethylases that regulate gene expression throughout the genome.Using mouse models that distinguish between chromosomal and gonadal sex effects, sex chromosomes have been shown to impact sex-biased diseases such as obesity, hyperlipidemia, atherosclerosis, Alzheimer's disease, autoimmunity, and pulmonary hypertension. Many aspects of metabolism are sex-biased, from gene expression in metabolic tissues to the prevalence and presentation of cardiometabolic diseases. The influence of hormones produced by male and female gonads has been widely documented, but recent studies have begun to elucidate the impact of genetic sex (XX or XY chromosomes) on cellular and organismal metabolism. XX and XY cells have differential gene dosage conferred by specific genes that escape X chromosome inactivation or the presence of Y chromosome genes that are absent from XX cells. Studies in mouse models that dissociate chromosomal and gonadal sex have uncovered mechanisms for sex-biased epigenetic, transcriptional, and post-transcriptional regulation of gene expression in conditions such as obesity, atherosclerosis, pulmonary hypertension, autoimmune disease, and Alzheimer's disease. Many aspects of metabolism are sex-biased, from gene expression in metabolic tissues to the prevalence and presentation of cardiometabolic diseases. The influence of hormones produced by male and female gonads has been widely documented, but recent studies have begun to elucidate the impact of genetic sex (XX or XY chromosomes) on cellular and organismal metabolism. XX and XY cells have differential gene dosage conferred by specific genes that escape X chromosome inactivation or the presence of Y chromosome genes that are absent from XX cells. Studies in mouse models that dissociate chromosomal and gonadal sex have uncovered mechanisms for sex-biased epigenetic, transcriptional, and post-transcriptional regulation of gene expres