Sex Chromosome Dosage Effects On Gene Expression In Humans

Raznahan, Armin; Parikshak, Neelroop N.; Chandran, Vijayendran; Blumenthal, Jonathan D.; Clasen, Liv S.; Alexander-Bloch, Aaron; Zinn, Andrew R.; Wangsa, Danny; Wise, Jasen; Murphy, Declan; Bolton, Patrick; Ried, Thomas; Ross, Judith L.; Giedd, Jay N.; Geschwind, Daniel H.

doi:10.1101/137752

Cited by 17 publications

(21 citation statements)

References 36 publications

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“…[11,[27][28][29][30] Sex-specific methylation differences have also been reported [31] and interestingly, the patterns depend, at least in part, on the sex chromosome complement. [33] The central challenge now is to link expression and epigenetic sex biases to human phenotypes and disease susceptibilities. [33] The central challenge now is to link expression and epigenetic sex biases to human phenotypes and disease susceptibilities.…”

Section: Sexual Dimorphisms In Human Health and Disease Come To The Forementioning

confidence: 99%

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

Engel

2018

BioEssays

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Sex-specific transcriptional and epigenomic profiles are detectable in the embryo very soon after fertilization. I propose that in male (XY) and female (XX) pre-implantation embryos sex chromosomes establish sexually dimorphic interactions with the autosomes, before overt differences become apparent and long before gonadogenesis. Lineage determination restricts expression biases between the sexes, but the epigenetic differences are less constrained and can be perpetuated, accounting for dimorphisms that arise later in life. In this way, sexual identity is registered in the epigenome very early in development. As development progresses, sex-specific regulatory modules are harbored within shared transcriptional networks that delineate common traits. In reviewing this field, I propose that analyzing the mechanisms for sexual dimorphisms at the molecular and biochemical level and incorporating developmental and environmental factors will lead to a greater understanding of sex differences in health and disease. Also see the video abstract here: https://youtu.be/9BPlbrHtkHQ.

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Section: Sexual Dimorphisms In Human Health and Disease Come To The Forementioning

confidence: 99%

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

Engel

2018

BioEssays

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“…Eutherian females have higher levels of this protein and its mRNA than eutherian males [13,15]. However, eutherian males also carry UTY [16], the homologue of KDM6A on the Y chromosome, and its expression level correlates with the number of Y chromosomes [14]. X chromosome genes with a Y chromosome paralogue generally have a role in transcription, translation and nucleic acid binding [17] and hence are central to regulation of gene expression during development, immune function, cell proliferation and differentiation and tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

“…The KDM6A gene is located on the X chromosome in eutherian mammals [11]. Although not located in the pseudoautosomal region, KDM6A escapes X-inactivation [12,13] and its level of expression reflects the number of X chromosomes [14]. Eutherian females have higher levels of this protein and its mRNA than eutherian males [13,15].…”

Section: Introductionmentioning

confidence: 99%

Lysine demethylases KDM6A and UTY: The X and Y of histone demethylation

Gažová

Lengeling

Summers

2019

Molecular Genetics and Metabolism

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Histone demethylases remove transcriptional repressive marks from histones in the nucleus. KDM6A (also known as UTX) is a lysine demethylase which acts on the trimethylated lysine at position 27 in histone 3. The KDM6A gene is located on the X chromosome but escapes X inactivation even though it is not located in the pseudoautosomal region. There is a homologue of KDM6A on the Y chromosome, known as UTY. UTY was thought to have lost its demethylase activity and to represent a non-functional remnant of the ancestral KDM6A gene. However, results with knockout mice suggest that the gene is expressed and the protein performs some function within the cell. Female mice with homozygous deletion of Kdm6a do not survive, but hemizygous males are viable, attributed to the presence of the Uty gene. KDM6A is mutated in the human condition Kabuki syndrome type 2 (OMIM 300867) and in many cases of cancer. The amino acid sequence of KDM6A has been conserved across animal phyla, although it is only found on the X chromosome in eutherian mammals. In this review, we reanalyse existing data from various sources (protein sequence comparison, evolutionary genetics, transcription factor binding and gene expression analysis) to determine the function, expression and evolution of KDM6A and UTY and show that UTY has a functional role similar to KDM6A in metabolism and development.

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“…2010; Raznahan et al. 2018). Moreover, the parental origin of the single X chromosome in humans with Turner syndrome (45,X) impacts prenatal survival and the severity of postnatal phenotypes, indicating parent‐of‐origin epigenetic effects (Sagi et al.…”

Section: Discussionmentioning

confidence: 99%

Haldane's rule in the placenta: Sex‐biased misregulation of the Kcnq1 imprinting cluster in hybrid mice

2020

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Hybrid phenotypes that contribute to postzygotic reproductive isolation often exhibit pronounced asymmetry, both between reciprocal crosses and between the sexes in accordance with Haldane's rule. Inviability in mammalian hybrids is associated with parent‐of‐origin placental growth abnormalities for which misregulation of imprinted gene (IGs) is the leading candidate mechanism. However, direct evidence for the involvement of IGs in hybrid growth dysplasia is limited. We used transcriptome and reduced representation bisulfite sequencing to conduct the first genome‐scale assessment of the contribution of IGs to parent‐of‐origin placental growth dysplasia in the cross between the house mouse (Mus musculus domesticus) and the Algerian mouse (Mus spretus). IGs with transgressive expression and methylation were concentrated in the Kcnq1 cluster, which contains causal genes for prenatal growth abnormalities in mice and humans. Hypermethylation of the cluster's imprinting control region, and consequent misexpression of the genes Phlda2 and Ascl2, is a strong candidate mechanism for transgressive placental undergrowth. Transgressive placental and gene regulatory phenotypes, including expression and methylation in the Kcnq1 cluster, were more extreme in hybrid males. Although consistent with Haldane's rule, male‐biased defects are unexpected in rodent placenta because the X‐chromosome is effectively hemizygous in both sexes. In search of an explanation, we found evidence of leaky imprinted (paternal) X‐chromosome inactivation in hybrid female placenta, an epigenetic disturbance that may buffer females from the effects of X‐linked incompatibilities to which males are fully exposed. Sex differences in chromatin structure on the X and sex‐biased maternal effects are nonmutually exclusive alternative explanations for adherence to Haldane's rule in hybrid placenta. The results of this study contribute to understanding the genetic basis of hybrid inviability in mammals, and the role of IGs in speciation.

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Sex Chromosome Dosage Effects On Gene Expression In Humans

Cited by 17 publications

References 36 publications

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

Lysine demethylases KDM6A and UTY: The X and Y of histone demethylation

Haldane's rule in the placenta: Sex‐biased misregulation of the Kcnq1 imprinting cluster in hybrid mice

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