@article{ca5743d86db444349ed420d7e75c6173,
title = "Differential Regulation of Mouse Hippocampal Gene Expression Sex Differences by Chromosomal Content and Gonadal Sex",
abstract = "Common neurological disorders, like Alzheimer{\textquoteright}s disease (AD), multiple sclerosis (MS), and autism, display profound sex differences in prevalence and clinical presentation. However, sex differences in the brain with health and disease are often overlooked in experimental models. Sex effects originate, directly or indirectly, from hormonal or sex chromosomal mechanisms. To delineate the contributions of genetic sex (XX v. XY) versus gonadal sex (ovaries v. testes) to the epigenomic regulation of hippocampal sex differences, we used the Four Core Genotypes (FCG) mouse model which uncouples chromosomal and gonadal sex. Transcriptomic and epigenomic analyses of ~ 12-month-old FCG mouse hippocampus, revealed genomic context-specific regulatory effects of genotypic and gonadal sex on X- and autosome-encoded gene expression and DNA modification patterns. X-chromosomal epigenomic patterns, classically associated with X-inactivation, were established almost entirely by genotypic sex, independent of gonadal sex. Differences in X-chromosome methylation were primarily localized to gene regulatory regions including promoters, CpG islands, CTCF binding sites, and active/poised chromatin, with an inverse relationship between methylation and gene expression. Autosomal gene expression demonstrated regulation by both genotypic and gonadal sex, particularly in immune processes. These data demonstrate an important regulatory role of sex chromosomes, independent of gonadal sex, on sex-biased hippocampal transcriptomic and epigenomic profiles. Future studies will need to further interrogate specific CNS cell types, identify the mechanisms by which sex chromosomes regulate autosomes, and differentiate organizational from activational hormonal effects.",
keywords = "Epigenome, Four core genotypes, Hippocampus, Sex chromosome, Sex difference, Transcriptome",
author = "Oca{\~n}as, {Sarah R.} and Ansere, {Victor A.} and Tooley, {Kyla B.} and Niran Hadad and Chucair-Elliott, {Ana J.} and Stanford, {David R.} and Shannon Rice and Benjamin Wronowski and Pham, {Kevin D.} and Hoffman, {Jessica M.} and Austad, {Steven N.} and Stout, {Michael B.} and Freeman, {Willard M.}",
note = "Funding Information: This work was supported by grants from the National Institutes of Health (NIH) P30AG050911, R01AG059430, R56AG067754, T32AG052363, F31AG064861, K99AG059920, P30EY021725, P30AG050886, R21AG058811, R01AG057434, R01AG070035, R01AG069742, Oklahoma Center for Adult Stem Cell Research (OCASCR), a program of the Oklahoma Tobacco Settlement Endowment Trust, BrightFocus Foundation (M2020207), and Presbyterian Health Foundation. This work was also supported in part by the MERIT award I01BX003906 and a Shared Equipment Evaluation Program (ShEEP) award ISIBX004797 from the United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Development Service. The authors would also like to thank the Clinical Genomics Center (OMRF) for assistance and instrument usage. The authors also acknowledge Robyn Berent (administrative support and lab management), Adeline Machalinski (animal colony management), Ashley Martin (manuscript review), and Hunter Porter (scientific discussions). Funding Information: This work was supported by grants from the National Institutes of Health (NIH) P30AG050911, R01AG059430, R56AG067754, T32AG052363, F31AG064861, P30EY021725, P30AG050886, R21AG058811, R01AG057434, R01AG070035, R01AG069742, K99AG059920, Oklahoma Center for Adult Stem Cell Research (OCASCR), a program of the Oklahoma Tobacco Settlement Endowment Trust, BrightFocus Foundation (M2020207), and Presbyterian Health Foundation. This work was also supported in part by the MERIT award I01BX003906 and a Shared Equipment Evaluation Program (ShEEP) award ISIBX004797 from the United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Development Service. Publisher Copyright: {\textcopyright} 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
year = "2022",
month = aug,
doi = "10.1007/s12035-022-02860-0",
language = "English (US)",
volume = "59",
pages = "4669--4702",
journal = "Molecular Neurobiology",
issn = "0893-7648",
publisher = "Humana Press",
number = "8",
}