Tissue-specific sex differences in human gene expression

Abstract Despite extensive sex differences in human complex traits and disease, the male and female genomes differ only in the sex chromosomes. This implies that most sex-differentiated traits are the result of differences in the expression of genes that are common to both sexes. While sex differences in gene expression have been observed in a range of different tissues, the biological mechanisms for tissue-specific sex differences (TSSDs) in gene expression are not well understood. A total of 30 640 autosomal and 1021 X-linked transcripts were tested for heterogeneity in sex difference effect sizes in n = 617 individuals across 40 tissue types in Genotype–Tissue Expression (GTEx). This identified 65 autosomal and 66 X-linked TSSD transcripts (corresponding to unique genes) at a stringent significance threshold. Results for X-linked TSSD transcripts showed mainly concordant direction of sex differences across tissues and replicate previous findings. Autosomal TSSD transcripts had mainly discordant direction of sex differences across tissues. The top cis-expression quantitative trait loci (eQTLs) across tissues for autosomal TSSD transcripts are located a similar distance away from the nearest androgen and estrogen binding motifs and the nearest enhancer, as compared to cis-eQTLs for transcripts with stable sex differences in gene expression across tissue types. Enhancer regions that overlap top cis-eQTLs for TSSD transcripts, however, were found to be more dispersed across tissues. These observations suggest that androgen and estrogen regulatory elements in a cis region may play a common role in sex differences in gene expression, but TSSD in gene expression may additionally be due to causal variants located in tissue-specific enhancer regions.

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A modified pod specific promoter for high level heterologous expression of genes in legumes

Legume Research - An International Journal ◽

10.18805/lr-4073 ◽

2019 ◽

Author(s):

Aravind Kumar Konda ◽

Pallavi Singh ◽

Khela Ram Soren ◽

Narendra Pratap Singh

Keyword(s):

Gene Expression ◽

Regulatory Elements ◽

Specific Gene ◽

Specific Expression ◽

Tissue Specific ◽

Cis Acting ◽

Inducible Promoters ◽

Expression Of Genes ◽

Enhanced Expression ◽

High Level

Promoters are cis-acting regulatory elements that are usually present upstream to the coding sequences and determine the gene expression. Deployment of tissue specific and inducible promoters are constantly increasing for development of successful and stable multiple transgenic plants. To this end, as a strategy for enhanced expression of cis or transgenes, promoter engineering of the native msg promoter from soya bean has been carried out for executing pod specific expression of genes. Cis regulatory elements such as 5’UTR and poly (A) tract have been incorporated for imparting mRNA stability and translational enhancement to generate the modified 1.285 Kb pod specific promoter. Further to attain transcriptional enhancement the modified promoter has been cloned to generate Bi-directional Duplex Promoters (BDDP). The engineered msg promoter gene constructs can be deployed for high level tissue specific gene expression of cis/trans genes along with chosen terminator in chickpea. soybean and other legumes as well.

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Local genetic effects on gene expression across 44 human tissues

10.1101/074450 ◽

2016 ◽

Cited By ~ 21

Author(s):

François Aguet ◽

Andrew A. Brown ◽

Stephane E. Castel ◽

Joe R. Davis ◽

Pejman Mohammadi ◽

...

Keyword(s):

Gene Expression ◽

Complex Traits ◽

Large Scale ◽

Genetic Diseases ◽

Tissue Expression ◽

Specific Expression ◽

Tissue Specific ◽

Regulatory Variation ◽

Functional Variants ◽

Trait Locus

AbstractExpression quantitative trait locus (eQTL) mapping provides a powerful means to identify functional variants influencing gene expression and disease pathogenesis. We report the identification of cis-eQTLs from 7,051 post-mortem samples representing 44 tissues and 449 individuals as part of the Genotype-Tissue Expression (GTEx) project. We find a cis-eQTL for 88% of all annotated protein-coding genes, with one-third having multiple independent effects. We identify numerous tissue-specific cis-eQTLs, highlighting the unique functional impact of regulatory variation in diverse tissues. By integrating large-scale functional genomics data and state-of-the-art fine-mapping algorithms, we identify multiple features predictive of tissue-specific and shared regulatory effects. We improve estimates of cis-eQTL sharing and effect sizes using allele specific expression across tissues. Finally, we demonstrate the utility of this large compendium of cis-eQTLs for understanding the tissue-specific etiology of complex traits, including coronary artery disease. The GTEx project provides an exceptional resource that has improved our understanding of gene regulation across tissues and the role of regulatory variation in human genetic diseases.

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Epigenomic Profiling and Single-Nucleus-RNA-Seq Reveal Cis-Regulatory Elements in Human Retina, Macula and RPE and Non-Coding Genetic Variation

10.1101/412361 ◽

2018 ◽

Cited By ~ 2

Author(s):

Timothy J. Cherry ◽

Marty G. Yang ◽

David A. Harmin ◽

Peter Tao ◽

Andrew E. Timms ◽

...

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Complex Traits ◽

Retinal Pigment ◽

Regulatory Elements ◽

Human Vision ◽

Specific Gene ◽

Tissue Specific ◽

Complex Disorders ◽

Regulatory Variation

ABSTRACTCis-regulatory elements (CREs) orchestrate the dynamic and diverse transcriptional programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. However, the cellular complexity of the human brain has largely precluded the identification of functional regulatory variation within the human CNS. We took advantage of the retina, a well-characterized region of the CNS with reduced cellular heterogeneity, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive resource of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines the regulatory elements with the potential to contribute to mendelian and complex disorders of human vision.

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Mapping the cis-regulatory architecture of the human retina reveals noncoding genetic variation in disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922501117 ◽

2020 ◽

Vol 117 (16) ◽

pp. 9001-9012 ◽

Cited By ~ 4

Author(s):

Timothy J. Cherry ◽

Marty G. Yang ◽

David A. Harmin ◽

Peter Tao ◽

Andrew E. Timms ◽

...

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Complex Traits ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Regulatory Elements ◽

Human Vision ◽

Specific Gene ◽

Tissue Specific ◽

Complex Disorders

The interplay of transcription factors and cis-regulatory elements (CREs) orchestrates the dynamic and diverse genetic programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. We took advantage of the retina, a well-characterized region of the CNS known to be affected by pathogenic variants in CREs, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive analysis of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, and retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines regulatory elements with the potential to contribute to Mendelian and complex disorders of human vision.

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HCR-FlowFISH: A flexible CRISPR screening method to identify cis-regulatory elements and their target genes

10.1101/2020.05.11.078675 ◽

2020 ◽

Author(s):

SK Reilly ◽

SJ Gosai ◽

A Gutierrez ◽

JC Ulirsch ◽

M Kanai ◽

...

Keyword(s):

Gene Expression ◽

Target Genes ◽

Screening Method ◽

Cell Types ◽

Regulatory Elements ◽

Hybridization Chain Reaction ◽

Genome Wide ◽

Wide Range ◽

Causal Variants ◽

Endogenous Loci

AbstractCRISPR screens for cis-regulatory elements (CREs) have shown unprecedented power to endogenously characterize the non-coding genome. To characterize CREs we developed HCR-FlowFISH (Hybridization Chain Reaction Fluorescent In-Situ Hybridization coupled with Flow Cytometry), which directly quantifies native transcripts within their endogenous loci following CRISPR perturbations of regulatory elements, eliminating the need for restrictive phenotypic assays such as growth or transcript-tagging. HCR-FlowFISH accurately quantifies gene expression across a wide range of transcript levels and cell types. We also developed CASA (CRISPR Activity Screen Analysis), a hierarchical Bayesian model to identify and quantify CRE activity. Using >270,000 perturbations, we identified CREs for GATA1, HDAC6, ERP29, LMO2, MEF2C, CD164, NMU, FEN1 and the FADS gene cluster. Our methods detect subtle gene expression changes and identify CREs regulating multiple genes, sometimes at different magnitudes and directions. We demonstrate the power of HCR-FlowFISH to parse genome-wide association signals by nominating causal variants and target genes.

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A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome

10.1101/563379 ◽

2019 ◽

Cited By ~ 2

Author(s):

Tom G Richardson ◽

Gibran Hemani ◽

Tom R Gaunt ◽

Caroline L Relton ◽

George Davey Smith

Keyword(s):

Gene Expression ◽

Genetic Variants ◽

Complex Traits ◽

Mendelian Randomization ◽

Drug Repositioning ◽

Association Studies ◽

Thyroid Tissue ◽

Genome Wide Association Studies ◽

Tissue Specific ◽

Genome Wide

AbstractBackgroundDeveloping insight into tissue-specific transcriptional mechanisms can help improve our understanding of how genetic variants exert their effects on complex traits and disease. By applying the principles of Mendelian randomization, we have undertaken a systematic analysis to evaluate transcriptome-wide associations between gene expression across 48 different tissue types and 395 complex traits.ResultsOverall, we identified 100,025 gene-trait associations based on conventional genome-wide corrections (P < 5 × 10−08) that also provided evidence of genetic colocalization. These results indicated that genetic variants which influence gene expression levels in multiple tissues are more likely to influence multiple complex traits. We identified many examples of tissue-specific effects, such as genetically-predicted TPO, NR3C2 and SPATA13 expression only associating with thyroid disease in thyroid tissue. Additionally, FBN2 expression was associated with both cardiovascular and lung function traits, but only when analysed in heart and lung tissue respectively.We also demonstrate that conducting phenome-wide evaluations of our results can help flag adverse on-target side effects for therapeutic intervention, as well as propose drug repositioning opportunities. Moreover, we find that exploring the tissue-dependency of associations identified by genome-wide association studies (GWAS) can help elucidate the causal genes and tissues responsible for effects, as well as uncover putative novel associations.ConclusionsThe atlas of tissue-dependent associations we have constructed should prove extremely valuable to future studies investigating the genetic determinants of complex disease. The follow-up analyses we have performed in this study are merely a guide for future research. Conducting similar evaluations can be undertaken systematically at http://mrcieu.mrsoftware.org/Tissue_MR_atlas/.

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Sex Differences in the Epigenome: A Cause or Consequence of Sexual Differentiation of the Brain?

Genes ◽

10.3390/genes10060432 ◽

2019 ◽

Vol 10 (6) ◽

pp. 432 ◽

Cited By ~ 9

Author(s):

Bruno Gegenhuber ◽

Jessica Tollkuhn

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Sexual Differentiation ◽

Hormone Receptors ◽

Neurological Diseases ◽

Activity Patterns ◽

Regulatory Elements ◽

The Body ◽

Epigenetic Mechanism ◽

The Brain

Females and males display differences in neural activity patterns, behavioral responses, and incidence of psychiatric and neurological diseases. Sex differences in the brain appear throughout the animal kingdom and are largely a consequence of the physiological requirements necessary for the distinct roles of the two sexes in reproduction. As with the rest of the body, gonadal steroid hormones act to specify and regulate many of these differences. It is thought that transient hormonal signaling during brain development gives rise to persistent sex differences in gene expression via an epigenetic mechanism, leading to divergent neurodevelopmental trajectories that may underlie sex differences in disease susceptibility. However, few genes with a persistent sex difference in expression have been identified, and only a handful of studies have employed genome-wide approaches to assess sex differences in epigenomic modifications. To date, there are no confirmed examples of gene regulatory elements that direct sex differences in gene expression in the brain. Here, we review foundational studies in this field, describe transcriptional mechanisms that could act downstream of hormone receptors in the brain, and suggest future approaches for identification and validation of sex-typical gene programs. We propose that sexual differentiation of the brain involves self-perpetuating transcriptional states that canalize sex-specific development.

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STAT5 regulation of sex-dependent hepatic CpG methylation at distal regulatory elements mapping to sex-biased genes

Molecular and Cellular Biology ◽

10.1128/mcb.00166-20 ◽

2020 ◽

Author(s):

Pengying Hao ◽

David J. Waxman

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Mouse Liver ◽

Regulatory Elements ◽

Cpg Methylation ◽

Sex Bias ◽

Liver Chromatin ◽

Differential Gene ◽

Genomic Regions ◽

Distal Regulatory Elements

Growth hormone-activated STAT5b is an essential regulator of sex-differential gene expression in mouse liver, however, its impact on hepatic gene expression and epigenetic responses is poorly understood. Here, we found a substantial, albeit incomplete loss of liver sex bias in hepatocyte-specific STAT5a/STAT5b (collectively, STAT5)-deficient mouse liver. In male liver, many male-biased genes were down regulated in direct association with the loss of STAT5 binding; many female-biased genes, which show low STAT5 binding, were de-repressed, indicating an indirect mechanism for repression by STAT5. Extensive changes in CpG-methylation were seen in STAT5-deficient liver, where sex differences were abolished at 88% of ∼1,500 sex-differentially methylated regions, largely due to increased DNA methylation upon STAT5 loss. STAT5-dependent CpG-hypomethylation was rarely found at proximal promoters of STAT5-dependent genes. Rather, STAT5 primarily regulated the methylation of distal enhancers, where STAT5 deficiency induced widespread hypermethylation at genomic regions enriched for accessible chromatin, enhancer histone marks (H3K4me1, H3K27ac), STAT5 binding, and DNA motifs for STAT5 and other transcription factors implicated in liver sex differences. Thus, the sex-dependent binding of STAT5 to liver chromatin is closely linked to the sex-dependent demethylation of distal regulatory elements linked to STAT5-dependent genes important for liver sex bias.

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Phytochrome signal-transduction: characterization of pathways and isolation of mutants

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1995.0139 ◽

1995 ◽

Vol 350 (1331) ◽

pp. 67-74 ◽

Cited By ~ 13

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Red Light ◽

Signal Transduction Pathway ◽

Regulatory Elements ◽

Signal Transduction Pathways ◽

Expression Of Genes ◽

Genes Encoding ◽

Regulated Gene Expression ◽

Dependent Pathway

The study of phytochrome signalling has yielded a wealth of data describing both the perception of light by the receptor, and the terminal steps in phytochrome-regulated gene expression by a number of transcription factors. We are now focusing on establishing the intervening steps linking phytochrome photoactivation to gene expression, and the regulation and interactions of these signalling pathways. Recent work has utilized both a pharmacological approach in phototrophic soybean suspension cultures and microinjection techniques in tomato to establish three distinct phytochrome signal-transduction pathways: (i) a calcium-dependent pathway that regulates the expression of genes encoding the chlorophyll a/b binding protein ( CAB ) and other components of photosystem II; (ii) a cGMP-dependent pathway that regulates the expression of the gene encoding chalcone synthase ( CHS ) and the production of anthocyanin pigments; and (iii) a pathway dependent upon both calcium and cGMP that regulates the expression of genes encoding components of photosystem I and is necessary for the production of mature chloroplasts. To study the components and the regulation of phytochrome signal-transduction pathways, mutants with altered photomorphogenic responses have been isolated by a number of laboratories. However, with several possible exceptions, little real progress has been made towards the isolation of mutants in positive regulatory elements of the phytochrome signal-transduction pathway. We have characterized a novel phytochrome A (phyA)-mediated far-red light (FR) response in Arabidopsis seedlings which we are currently using to screen for specific phyA signal-transduction mutants.

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Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases

Scientific Reports ◽

10.1038/srep15145 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 98

Author(s):

Jialiang Yang ◽

◽

Tao Huang ◽

Francesca Petralia ◽

Quan Long ◽

...

Keyword(s):

Gene Expression ◽

Complex Disease ◽

Principal Component ◽

Tissue Expression ◽

Whole Body ◽

Disease Genes ◽

Related Gene ◽

Tissue Specific ◽

Age Related ◽

Holistic Understanding

Abstract Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project. In general, we find the aging gene expression signatures are very tissue specific. However, enrichment for some well-known aging components such as mitochondria biology is observed in many tissues. Different levels of cross-tissue synchronization of age-related gene expression changes are observed and some essential tissues (e.g., heart and lung) show much stronger “co-aging” than other tissues based on a principal component analysis. The aging gene signatures and complex disease genes show a complex overlapping pattern and only in some cases, we see that they are significantly overlapped in the tissues affected by the corresponding diseases. In summary, our analyses provide novel insights to the co-regulation of age-related gene expression in multiple tissues; it also presents a tissue-specific view of the link between aging and age-related diseases.

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