Sexual dimorphism in gene expression and regulatory networks across human tissues

Chen, Cho-Yi; Lopes‐Ramos, Camila M.; Kuijjer, Marieke L.; Paulson, Joseph N.; Sonawane, Abhijeet R.; Fagny, Maud; Platig, John; Glass, Kimberly; Quackenbush, John; DeMeo, Dawn L.

doi:10.1101/082289

Cited by 27 publications

(34 citation statements)

References 75 publications

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“…Studying the transcriptome is a very powerful hypothesis-free approach to elucidate the molecular mechanisms underlying diseases and phenotypes. In this study, we analyzed the differential transcriptomics of human airway epithelium at baseline and in response to smoking between males and females u. and found that 1) smoking has a large and reproducible effect on sexually dimorphic gene expression were noted in the breast, skin, thyroid, brain, and adipose tissues while the least dimorphic was the gastrointestinal tract 18 . Multiple other studies in single cell or tissue types have confirmed to varying extents the large transcription differences between the two sexes [19][20][21][22] .…”

Section: Discussionmentioning

confidence: 99%

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking

Yang

Shi

Ding

et al. 2019

Preprint

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Epidemiological studies have shown that female smokers are at higher risk of chronic obstructive pulmonary disease (COPD). Female patients have worse symptoms and health status and increased risk of exacerbations. We determined the differences in the transcriptome of the airway epithelium between males and females at baseline and in response to smoking. We processed public gene expression data of human airway epithelium into a discovery cohort of 211 subjects (never smokers n=68; current smokers n=143) and two replication cohorts of 104 subjects (21 never, 52 current, and 31 former smokers) and 238 subjects (99 current and 139 former smokers.We analyzed gene differential expression with smoking status, sex, and smoking-by-sex interaction and used network approaches for modules' level analyses. We identified and replicated two differentially expressed modules between the sexes in response to smoking with genes located throughout the autosomes and not restricted to sex chromosomes. The two modules were enriched in autophagy (up-regulated in female smokers) and response to virus and type 1 interferon signaling pathways which were down-regulated in female smokers compared to males. The results offer insights into the molecular mechanisms of the sexually dimorphic COPD risk and presentation potentially enabling a precision medicine approach to COPD.

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Section: Discussionmentioning

confidence: 99%

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking

Yang

Shi

Ding

et al. 2019

Preprint

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“…MEF2C is also a known downstream target of the androgen receptor (AR), thus making it highly susceptible to androgen-dependent transcriptional influence 43 . MEF2C is also one of the most important transcription factor genes influencing sex differences in human brain gene expression -MEF2C differentially targets genes as a function of sex, and the magnitude of this sex-differential targeting explains a large percentage of variance in sex differences in gene expression of its putative targets 44 . Our work further underscores MEF2C's involvement in male-specific mechanisms behind atypical neurodevelopment, and particularly highlights how MEF2C could be one of many candidates behind fetal programming effects of androgens on developing social brain circuits such as the DMN.…”

Section: Discussionmentioning

confidence: 99%

“…MEF2C is also known to be a downstream target of the androgen receptor 43 . As a transcription factor itself, MEF2C is also known to differentially target other genes as a function of sex and the degree of such sex-differential targeting explains a substantial amount of variance in sex-differential expression 44 . Confirming DHT-upregulation of MEF2C expression we ran a follow-up experiment using qPCR and found that indeed the upregulation of MEF2C by DHT in the RNA-seq data is replicated using qPCR on three additional independent cell lines and (t = 3.73, p = 0.003, replication Bayes Factor = 164) ( Figure 3B-C).…”

Section: Figure 2: Synaptic Enrichments Of Dht-dysregulated Genes Andmentioning

confidence: 99%

Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems

Lombardo

Auyeung

Pramparo

et al. 2018

Preprint

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Many early-onset neurodevelopmental conditions such as autism affect males more frequently than females and affect corresponding domains such as social cognition, social-communication, language, emotion, and reward. Testosterone is well-known for its role as a sex-related biological mechanism and affects these conditions and domains of functioning. Developmentally, testosterone may sex-differentially impact early fetal brain development by influencing early neuronal development and synaptic mechanisms behind cortical circuit formation, particularly for circuits that later develop specialized roles in such cognitive domains. Here we find that variation in fetal testosterone (FT) exerts sex-specific effects on later adolescent functional connectivity between social brain default mode network (DMN) subsystems. Increased FT is associated with dampening of functional connectivity between DMN subsystems in adolescent males, but has no effect in females. To isolate specific prenatal neurobiological mechanisms behind this effect, we examined changes in gene expression identified following a treatment with a potent androgen, dihydrotestosterone (DHT) in an in-vitro model of human neural stem cell (hNSC). We previously showed that DHT-dysregulates genes enriched with known syndromic causes for autism and intellectual disability. DHT dysregulates genes in hNSCs involved in early neurodevelopmental processes such as neurogenesis, cell differentiation, regionalization, and pattern specification. A significant number of these DHT-dysregulated genes shows spatial expression patterns in the adult brain that highly correspond to the spatial layout of the cortical midline DMN subsystem. These DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation/inhibition imbalance. Focusing on MEF2C, we find replicable upregulation of expression after DHT treatment as well as dysregulated expression in induced pluripotent stem cells and neurons of individuals with autism. This work highlights sexspecific prenatal androgen influence on social brain DMN circuitry and autism-related mechanisms and suggests that such influence may impact early neurodevelopmental processes (e.g., neurogenesis, cell differentiation) and later developing synaptic processes.

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“…al. (34), which were modeled on data from the Genotype-Tissue Expression (GTEx) project (35). For the colon cancer networks, we reconstructed gene regulatory networks for each sample as shown in Figure 1.…”

Section: Differential Targeting Of Biological Pathways In Males and Fmentioning

confidence: 99%

Gene regulatory network analysis identifies sex-linked differences in colon cancer drug metabolism processes

Lopes‐Ramos

Kuijjer

Ogino

et al. 2018

Preprint

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Significant sex differences are observed in colon cancer, and understanding these differences is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. We used both transcript-based and gene regulatory network methods to analyze RNA-Seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and found no significant sex differences except for sex-chromosome genes. We then inferred patient-specific gene regulatory networks, and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset that included 1,193 patients from five independent studies. While targeting of the drug metabolism pathway did not change the overall survival for males treated with adjuvant chemotherapy, females with greater targeting had an increase in 10-year overall survival probability, with 89% (95% CI: 78%-100%) survival compared to 61% (95% CI: 45%-82%) for women with lower targeting, respectively (p=0.034).Our network analysis uncovered patterns of transcriptional regulation that differentiate male and female colon cancer. Most importantly, targeting of the drug metabolism pathway was predictive of survival in women who received adjuvant chemotherapy. This network-based approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.

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Sexual dimorphism in gene expression and regulatory networks across human tissues

Cited by 27 publications

References 75 publications

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking

Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems

Gene regulatory network analysis identifies sex-linked differences in colon cancer drug metabolism processes

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