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Title: Gender-affirming hormone therapy induces specific DNA methylation changes in blood.
Austin Authors: Shepherd, Rebecca;Bretherton, Ingrid ;Pang, Ken;Mansell, Toby;Czajko, Anna;Kim, Bowon;Vlahos, Amanda;Zajac, Jeffrey D ;Saffery, Richard;Cheung, Ada S ;Novakovic, Boris
Affiliation: Endocrinology
Medicine (University of Melbourne)
Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia
Molecular Immunity, Infection and Immunity Theme, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia
Brain and Mitochondrial Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia
Department of Adolescent Medicine, Royal Children's Hospital, Parkville, VIC, Australia
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
Issue Date: 2022
Date: 2022
Publication information: Clinical Epigenetics 2022; 14(1): 24
Abstract: DNA methylation is an epigenetic mark that is influenced by underlying genetic profile, environment, and ageing. In addition to X-linked DNA methylation, sex-specific methylation patterns are widespread across autosomal chromosomes and can be present from birth or arise over time. In individuals where gender identity and sex assigned at birth are markedly incongruent, as in the case of transgender people, feminization or masculinization may be sought through gender-affirming hormone therapy (GAHT). GAHT is a cornerstone of transgender care, yet no studies to date have investigated its effect on genome-wide methylation. We profiled genome-wide DNA methylation in blood of transgender women (n = 13) and transgender men (n = 13) before and during GAHT (6 months and 12 months into feminizing or masculinizing hormone therapy). We identified several thousand differentially methylated CpG sites (DMPs) (Δβ ≥ 0.02, unadjusted p value < 0.05) and several differentially methylated regions (DMRs) in both people undergoing feminizing and masculinizing GAHT, the vast majority of which were progressive changes over time. X chromosome and sex-specific autosomal DNA methylation patterns established in early development are largely refractory to change in association with GAHT, with only 3% affected (Δβ ≥ 0.02, unadjusted p value < 0.05). The small number of sex-specific DMPs that were affected by GAHT were those that become sex-specific during the lifetime, known as sex-and-age DMPs, including DMRs in PRR4 and VMP1 genes. The GAHT-induced changes at these sex-associated probes consistently demonstrated a shift towards the methylation signature of the GAHT-naïve opposite sex, and we observed enrichment of previously reported adolescence-associated methylation changes. We provide evidence for GAHT inducing a unique blood methylation signature in transgender people. This study advances our understanding of the complex interplay between sex hormones, sex chromosomes, and DNA methylation in the context of immunity. We highlight the need to broaden the field of 'sex-specific' immunity beyond cisgender males and cisgender females, as transgender people on GAHT exhibit a unique molecular profile.
DOI: 10.1186/s13148-022-01236-4
ORCID: 0000-0002-5623-9008
Journal: Clinical Epigenetics
PubMed URL: 35177097
Type: Journal Article
Subjects: DNA methylation
EPIC array
Appears in Collections:Journal articles

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