Isogenic mice exhibit sexually-dimorphic DNA methylation patterns across multiple tissues

McCormick, Helen; Young, Paul E.; Hur, Suzy S J; Booher, Keith; Chung, Hunter; Cropley, Jennifer E.; Giannoulatou, Eleni; Suter, Catherine M.

doi:10.1186/s12864-017-4350-x

Cited by 27 publications

(27 citation statements)

References 20 publications

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“…However, we have seen that no differentially methylated autosomal CpG sites between sexes, except one, contained androgen response elements, indicating that DNA methylation due to sex in the liver might be independent of testosterone. Moreover, sex hormones have been shown not to influence DNA methylation in human leukocytes or in mice liver ( 49 , 56 ). Notably, Mayne et al ( 45 ) reported that two-thirds of autosomal genes that were sex biased in the human liver were not under direct influence of sex hormones, which suggests there are other mechanisms driving hepatic sex differences, such as epigenetic factors.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels

García-Calzón

Perfilyev

Mello

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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ContextEpigenetics may contribute to sex-specific differences in human liver metabolism.ObjectiveTo study the impact of sex on DNA methylation and gene expression in human liver.Design/SettingCross-sectional, Kuopio Obesity Surgery Study.Participants/InterventionWe analyzed DNA methylation with the Infinium HumanMethylation450 BeadChip in liver of an obese population (34 males, 61 females). Females had a higher high-density lipoprotein (HDL)–cholesterol levels compared with males. Gene expression was measured with the HumanHT-12 Expression BeadChip in a subset of 42 participants.ResultsFemales displayed higher average methylation in the X-chromosome, whereas males presented higher methylation in autosomes. We found 9455 CpG sites in the X-chromosome and 33,205 sites in autosomes with significant methylation differences in liver between sexes (q < 0.05). When comparing our findings with published studies, 95% of the sex-specific differences in liver methylation in the X-chromosome were also found in pancreatic islets and brain, and 26 autosomal sites showed sex-specific methylation differences in the liver as well as in other human tissues. Furthermore, this sex-specific methylation profile in liver was associated with hepatic gene expression changes between males and females. Notably, females showed higher HDL-cholesterol levels, which were associated with higher KDM6A expression and epigenetic differences in human liver. Accordingly, silencing of KDM6A in cultured liver cells reduced HDL-cholesterol levels and APOA1 expression, which is a major component of HDL particles.ConclusionsHuman liver has a sex-specific methylation profile in both the X-chromosome and autosomes, which associates with hepatic gene expression changes and HDL-cholesterol. We identified KDM6A as a novel target that regulates HDL-cholesterol levels.

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Section: Discussionmentioning

confidence: 99%

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels

García-Calzón

Perfilyev

Mello

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…The most extensively profiled sexually dimorphic epigenetic mark is DNA methylation. Sex-specific methylation patterns have been observed in blood [74][75][76][77], placenta [78], liver [79][80][81][82], pancreas [83], muscle [84], heart [81], and brain [81,[85][86][87][88][89]. Sex differences in histone modifications have also been described, although thus far only in mouse brain [90,91].…”

Section: Sex Differences In Epigeneticsmentioning

confidence: 99%

Sex differences in cancer mechanisms

et al. 2020

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We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab-and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.

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“…The threshold of methylation differences is another parameter that can be tweaked in detecting sDMR. Therefore, we used a 20% threshold for methylation differences, which has been used by other groups in their studies of sex-biased methylation in mice [18,71].…”

Section: Methodology For Identifying Sdmc and Sdmr And Its Impact On mentioning

confidence: 99%

Sex Chromosomes and Sex Phenotype Contribute to Biased DNA Methylation in Mouse Liver

Zhuang

Galvez

Xiao

et al. 2020

Cells

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Sex biases in the genome-wide distribution of DNA methylation and gene expression levels are some of the manifestations of sexual dimorphism in mammals. To advance our understanding of the mechanisms that contribute to sex biases in DNA methylation and gene expression, we conducted whole genome bisulfite sequencing (WGBS) as well as RNA-seq on liver samples from mice with different combinations of sex phenotype and sex-chromosome complement. We compared groups of animals with different sex phenotypes, but the same genetic sexes, and vice versa, same sex phenotypes, but different sex-chromosome complements. We also compared sex-biased DNA methylation in mouse and human livers. Our data show that sex phenotype, X-chromosome dosage, and the presence of Y chromosome shape the differences in DNA methylation between males and females. We also demonstrate that sex bias in autosomal methylation is associated with sex bias in gene expression, whereas X-chromosome dosage-dependent methylation differences are not, as expected for a dosage-compensation mechanism. Furthermore, we find partial conservation between the repertoires of mouse and human genes that are associated with sex-biased methylation, an indication that gene function is likely to be an important factor in this phenomenon.

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Isogenic mice exhibit sexually-dimorphic DNA methylation patterns across multiple tissues

Cited by 27 publications

References 20 publications

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels

Sex differences in cancer mechanisms

Sex Chromosomes and Sex Phenotype Contribute to Biased DNA Methylation in Mouse Liver

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