Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans

Abstract

Background:Ageing is a heterogenous process characterised by cellular and molecular hallmarks, including changes to haematopoietic stem cells and is a primary risk factor for chronic diseases. X chromosome inactivation (XCI) randomly transcriptionally silences either the maternal or paternal X in each cell of 46, XX females to balance the gene expression with 46, XY males. Age acquired XCI-skew describes the preferential selection of cells across a tissue resulting in an imbalance of XCI, which is particularly prevalent in blood tissues of ageing females, and yet its clinical consequences are unknown.Methods:We assayed XCI in 1575 females from the TwinsUK population cohort using DNA extracted from whole blood. We employed prospective, cross-sectional, and intra-twin study designs to characterise the relationship of XCI-skew with molecular and cellular measures of ageing, cardiovascular disease risk, and cancer diagnosis.Results:We demonstrate that XCI-skew is independent of traditional markers of biological ageing and is associated with a haematopoietic bias towards the myeloid lineage. Using an atherosclerotic cardiovascular disease risk score, which captures traditional risk factors, XCI-skew is associated with an increased cardiovascular disease risk both cross-sectionally and within XCI-skew discordant twin pairs. In a prospective 10 year follow-up study, XCI-skew is predictive of future cancer incidence.Conclusions:Our study demonstrates that age acquired XCI-skew captures changes to the haematopoietic stem cell population and has clinical potential as a unique biomarker of chronic disease risk.Funding:KSS acknowledges funding from the Medical Research Council [MR/M004422/1 and MR/R023131/1]. JTB acknowledges funding from the ESRC [ES/N000404/1]. MM acknowledges funding from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London.

Stability of Genomic Imprinting and X-Chromosome Inactivation in the Aging Brain

“…6ii), consistent with previous studies 45 . This effect was not age-specific which contrast with the hematopoietic system for which aging-mediated enhanced skewing has been reported 77,33 . This may be explained by the differences in cell cycle turnover which is much higher during hematopoiesis than neurogenesis.…”

“…Although the molecular mechanisms underlying the initiation of X-chromosome inactivation (XCI) have been extensively elucidated, our understanding of the long-term maintenance of XCI throughout an organism’s lifespan remains limited. Recent investigations into aging, with a focus on the hematopoietic cell lineage, reveal an escalation in X-chromosome inactivation skewing, where one parental allele is preferentially inactivated 33 along with subtle alterations in DNA methylation patterns and gene expression across the X chromosome 34,35 . Interestingly, a separate study conducted in the brain, employing single-cell transcriptomics, unveiled an intriguing finding: Xist expression is observed to be upregulated in aged neurons located within the hypothalamus and hippocampus of female mice 36 .…”

Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

“…Overall, ever-smokers had no increased risk of mLOX (P=0.56); however, an increased risk was observed among ever-smokers for acquiring expanded mLOX with cell fraction ≥5% (OR=1.3 [1.2-1.5], P=6.9×10 −5 ) ( Supplementary Table S3 and Figure S4-5 ). The relationship between smoking and skewed X-inactivation has not been established, as smoking was suggested as a modulator for skewed XCI in the whole-blood tissue for women older than age 55 7 but not associated in the TwinsUK cohort 35 . No associations were observed between BMI and mLOX ( Supplementary Table S4 ).…”

Escape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable

“…On the other hand, sex differences may not directly reflect the allelic expression ratio of X-genes in a tissue. These limitations can be circumvented by using tissue samples exhibiting skewed XCI patterns–a common event in the female population [ 21 – 25 ]–which, as opposed to random XCI, enable detection and measurement of escape directly in skewed females (Note A in S1 Appendix ). This strategy has been employed, but either sample sizes were limited (e.g.…”