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Differential regulation of mouse hippocampal gene expression sex differences by chromosomal content and gonadal sex

View ORCID ProfileSarah R. Ocañas, View ORCID ProfileVictor A. Ansere, View ORCID ProfileKyla B. Tooley, View ORCID ProfileNiran Hadad, View ORCID ProfileAna J. Chucair-Elliott, David R. Stanford, Shannon Rice, Benjamin Wronowski, Jessica M. Hoffman, Steven N. Austad, View ORCID ProfileMichael B. Stout, View ORCID ProfileWillard M. Freeman
doi: https://doi.org/10.1101/2021.09.01.458115
Sarah R. Ocañas
1Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
2Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
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Victor A. Ansere
1Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
2Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
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Kyla B. Tooley
1Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
2Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
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Niran Hadad
2Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
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Ana J. Chucair-Elliott
1Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
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  • ORCID record for Ana J. Chucair-Elliott
David R. Stanford
1Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
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Shannon Rice
1Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
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Benjamin Wronowski
2Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
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Jessica M. Hoffman
3Department of Biology, The University of Alabama at Birmingham, Birmingham, AL USA
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Steven N. Austad
3Department of Biology, The University of Alabama at Birmingham, Birmingham, AL USA
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Michael B. Stout
4Aging & Metabolism Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
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Willard M. Freeman
1Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
5Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK USA
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  • For correspondence: bill-freeman@omrf.org
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Abstract

Sex differences in the brain as they relate to health and disease are often overlooked in experimental models. Many neurological disorders, like Alzheimer’s disease (AD), multiple sclerosis (MS), and autism, differ in prevalence between males and females. Sex differences originate either from differential gene expression on sex chromosomes or from hormonal differences, either directly or indirectly. To disentangle the relative contributions of genetic sex (XX v. XY) and gonadal sex (ovaries v. testes) to the regulation of hippocampal sex effects, we use the “sex-reversal” Four Core Genotype (FCG) mouse model which uncouples sex chromosome complement from gonadal sex. Transcriptomic and epigenomic analyses of hippocampal RNA and DNA from ∼12 month old FCG mice, reveals differential regulatory effects of sex chromosome content and gonadal sex on X- versus autosome-encoded gene expression and DNA modification patterns. Gene expression and DNA methylation patterns on the X chromosome were driven primarily by sex chromosome content, not gonadal sex. The majority of DNA methylation changes involved hypermethylation in the XX genotypes (as compared to XY) in the CpG context, with the largest differences in CpG islands, promoters, and CTCF binding sites. Autosomal gene expression and DNA modifications demonstrated regulation by sex chromosome complement and gonadal sex. These data demonstrate the importance of sex chromosomes themselves, independent of hormonal status, in regulating hippocampal sex effects. Future studies will need to further interrogate specific CNS cell types, identify the mechanisms by which sex chromosome regulate autosomes, and differentiate organizational from activational hormonal effects.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted September 02, 2021.
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Differential regulation of mouse hippocampal gene expression sex differences by chromosomal content and gonadal sex
Sarah R. Ocañas, Victor A. Ansere, Kyla B. Tooley, Niran Hadad, Ana J. Chucair-Elliott, David R. Stanford, Shannon Rice, Benjamin Wronowski, Jessica M. Hoffman, Steven N. Austad, Michael B. Stout, Willard M. Freeman
bioRxiv 2021.09.01.458115; doi: https://doi.org/10.1101/2021.09.01.458115
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Differential regulation of mouse hippocampal gene expression sex differences by chromosomal content and gonadal sex
Sarah R. Ocañas, Victor A. Ansere, Kyla B. Tooley, Niran Hadad, Ana J. Chucair-Elliott, David R. Stanford, Shannon Rice, Benjamin Wronowski, Jessica M. Hoffman, Steven N. Austad, Michael B. Stout, Willard M. Freeman
bioRxiv 2021.09.01.458115; doi: https://doi.org/10.1101/2021.09.01.458115

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