Tissue-specific sex differences in human gene expression

Kassam, Irfahan; Wu, Yang; Yang, Jian; Visscher, Peter M.; McRae, Allan F.

doi:10.1093/hmg/ddz090

Cited by 56 publications

(54 citation statements)

References 56 publications

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“…Two studies on sex differences in the liver transcriptome reported 844 and 1,249 sex-biased genes, respectively 22,23 . These numbers are in the same order of magnitude as what we report here for endothelial cells, highlighting that sex influences the transcriptome over variety of tissues, as underlined by work in the Genotype-Tissue Expression project 6,7 . Furthermore, sex differences in expression might also underlie differences between the sexes in response to stimuli or disease.…”

Section: Discussionsupporting

confidence: 80%

“…Transcriptomic studies of female and male (endothelial) cells shed light on differentially expressed genes (DEGs) between the sexes and their regulators, but few have been performed thus far on ECs 4 . Tissue-specific comparisons have been made using publicly available data from the Genotype-Tissue Expression project 6 , 7 , showing the importance of looking at sex differences in transcriptomics, but it may be difficult to extrapolate this to individual cell-types.…”

Section: Introductionmentioning

confidence: 99%

“…Genotype-Tissue Expression project 6,7 , showing the importance of looking at sex differences in transcriptomics, but it may be difficult to extrapolate this to individual cell-types.…”

mentioning

confidence: 99%

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Intrinsic transcriptomic sex differences in human endothelial cells at birth and in adults are associated with coronary artery disease targets

Hartman

Kapteijn

Haitjema

et al. 2020

Sci Rep

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Sex differences in endothelial cell (EC) biology may reflect intrinsic differences driven by chromosomes or sex steroid exposure and gender differences accumulated over life. We analysed EC gene expression data from boy-girl twins at birth and in non-twin adults to detect sex differences at different stages of life, and show that 14-25% of the EC transcriptome is sex-biased. By combining data from both stages of life, we identified sex differences that are present at birth and maintained throughout life, and those that are acquired over life. Promisingly, we found that genes that present with an acquired sex difference in ECs are more likely to be targets of sex steroids. Annotating both gene sets with data from multiple genome-wide association studies (GWAS) revealed that genes with an intrinsic sex difference in ECs are enriched for coronary artery disease GWAS hits. This study underscores the need for treating sex as a biological variable. Abbreviations CAD Coronary artery disease DEG Differentially expressed gene EC Endothelial cell HAEC Human aortic endothelial cell HUVEC Human umbilical vein endothelial cell GWAS Genome-wide association study Endothelial cells (ECs) are located at the innermost lining of all vessels and are responsible for circulatory homeostasis. ECs are implicated in a plethora of functions, such as water and nutrient transfer, inflammation, vascular tension, hemostasis, and angiogenesis 1. Differences in EC biology between the sexes have been described, indicating that sex is an important variable in EC biology 2. Studies focussing on functional differences, i.e. migration, proliferation, and shear stress response, imply sex differences in regulation of key endothelial pathways, such as the redox system 3-5. Differences between female and male cells might be present from birth onwards, or acquired later in life because of sex steroid exposure and gender differences. Pinpointing master regulators herein has been difficult, as differences between the sexes may be caused by sex hormones and/or sex chromosomes, which are difficult to study separately or to dissect. Transcriptomic studies of female and male (endothelial) cells shed light on differentially expressed genes (DEGs) between the sexes and their regulators, but few have been performed thus far on ECs 4. Tissue-specific comparisons have been made using publicly available data from the

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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Intrinsic transcriptomic sex differences in human endothelial cells at birth and in adults are associated with coronary artery disease targets

Hartman

Kapteijn

Haitjema

et al. 2020

Sci Rep

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“…Using this approach, Huggett and Stallings have identified a SNP associated with cocaine dependence and detected three genes (two loci) underlying this predisposition that displayed robust enrichment in numerous brain regions, including the hippocampus . Gene expression genetic analyses in the GTEx project show sex differences in genetic regulation of gene expression in both reproductive and nonreproductive tissues, providing an important means of evaluating the mechanisms through which sex‐specific genetic loci might act. This approach was recently used to interpret the male‐specific effects of an opioid dependence‐associated variant …”

Section: Sex Differences In Human Genomic Studies Of Addictionmentioning

confidence: 99%

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis

Datta

Schoenrock

Bubier

et al. 2020

Genes Brain and Behavior

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Despite substantial evidence for sex differences in addiction epidemiology, addiction‐relevant behaviors and associated neurobiological phenomena, the mechanisms and implications of these differences remain unknown. Genetic analysis in model organism is a potentially powerful and effective means of discovering the mechanisms that underlie sex differences in addiction. Human genetic studies are beginning to show precise risk variants that influence the mechanisms of addiction but typically lack sufficient power or neurobiological mechanistic access, particularly for the discovery of the mechanisms that underlie sex differences. Our thesis in this review is that genetic variation in model organisms are a promising approach that can complement these investigations to show the biological mechanisms that underlie sex differences in addiction.

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“…group 3, see above) and inactive in the tissues where they are not. For example, genes could be activated in ovary, but inactivated by regulatory mechanisms other than DNA methylation in RBCs (Campbell & Langlois 2018;Kassam et al 2019;Miragaia et al 2019).…”

Section: Discussionmentioning

confidence: 99%

The mechanisms underlying seasonal timing of breeding : a multi-level approach using bi-directional genomic selection on timing of egg-laying

Verhagen¹

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Table of contents Chapter 1 General introduction Chapter 2 Genetic and phenotypic responses to genomic selection for timing of breeding in a wild songbird Chapter 3 Temperature has a causal and plastic effect on timing of breeding in a small songbird Chapter 4 Exploration of tissue-specific gene expression patterns underlying timing of breeding in contrasting temperature environments in a songbird Chapter 5 Fine-tuning of seasonal timing of breeding is regulated downstream in the underlying neuro-endocrine system in a small songbird Chapter 6 Exploring temporal changes in DNA methylation and RNA expression in a small songbird-correlations within and between tissues Chapter 7 General discussion References Summary Samenvatting Curriculum vitae List of publications Acknowledgements WIAS Training and Education Statement CHAPTER 1 General introduction Chapter 1 10 Evolution and natural selection Evolution, the process that leads to the formation of and change in biological systems in response to their environment, has shaped life since its beginning and continues to do so. All organisms, simple and complex, evolve over different scales in both time and space. In general, evolution is described and studied as two distinct hierarchical processes; macroevolution and micro-evolution. Macro-evolution refers to the origin of new morphological forms, species and divisions of the taxonomic hierarchy above the species level, together with the origin of complex adaptations, such as the eye (Reznick & Ricklefs 2009), but on which I will not dwell further. In contrast, micro-evolution refers to the processes of adaptive modifications (i.e. through alteration in allele frequencies in gene pools) within and among populations, propelled by mutation, migration, genetic drift and natural selection. The latter, put first into words by, independently, both Charles Darwin (1859) and Alfred Russel Wallace (1858), is usually defined as the consequence of three organismal properties: (1) variation among organisms of a population, (2) differential reproduction, and (3) traits that are important for survival or reproduction show heritability (Darwin 1859; Wallace 1858).

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Tissue-specific sex differences in human gene expression

Cited by 56 publications

References 56 publications

Intrinsic transcriptomic sex differences in human endothelial cells at birth and in adults are associated with coronary artery disease targets

Intrinsic transcriptomic sex differences in human endothelial cells at birth and in adults are associated with coronary artery disease targets

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis

The mechanisms underlying seasonal timing of breeding : a multi-level approach using bi-directional genomic selection on timing of egg-laying

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