Project description:In individuals where gender identity and sex assigned at birth are markedly and consistently incongruent, as in the case of transgender people, feminisation or masculinisation may be sought through gender affirming hormone therapy (GAHT). In this study we profiled genome-wide DNA methylation in transgender women and transgender men, before and during GAHT (6 months and 12 months into hormone treatment).
Project description:The main objective was to carry out a global DNA methylation analysis in a population with gender incongruence before gender-affirming hormone treatment (GAHT), in comparison to a cisgender population.
Project description:The mammary gland is a hormone responsive organ and has been extensively studied under the influences of estrogen and progesterone. However, the molecular implications of androgen exposure in the normal breast remain elusive and unexplored, partially due to a lack of relevant tissue to study the functional consequences of androgen action. Transgender men are born female but identify as male, and many choose to undergo gender-affirming androgen therapy, which elicits wide-ranging masculinizing effects that help align their physical characteristics and gender identity. Here we perform single cell resolution profiling of androgen treated breast tissue from transgender men at the transcriptome, chromatin, and spatial level to elucidate the regulatory action of androgen. We show male-biased androgen receptor gene targets are specifically upregulated in androgen receptor expressing cell types, and that other sex-relevant changes are also initiated in cells lacking androgen receptor expression, through paracrine signaling cascades. We observe a functionally and structurally altered epithelium, shifts in immune populations and directed reduction of capillary vasculature. Finally, we discover evidence of the metabolic impact of androgen and demonstrate how the treatment induces fat loss by specifically targeting adipocyte function. This work provides a comprehensive and mechanistic characterization of the mammary tissue responses to androgen activity at single-cell resolution.
Project description:The main objective was to carry out a prospective global CpG (cytosine-phosphate-guanine) methylation analysis before vs. after six months of gender affirming hormone treatment (GAHT), in a transgender population vs. a cisgender population.
Project description:The mammary gland is a hormone responsive organ and has been extensively studied under the influences of estrogen and progesterone. However, the molecular implications of androgen exposure in the normal breast remain elusive and unexplored, partially due to a lack of relevant tissue to study the functional consequences of androgen action. Transgender men are born female but identify as male, and many choose to undergo gender-affirming androgen therapy, which elicits wide-ranging masculinizing effects that help align their physical characteristics and gender identity. Here we perform single cell resolution profiling of androgen treated breast tissue from transgender men at the transcriptome, chromatin, and spatial level to elucidate the regulatory action of androgen. We show male-biased androgen receptor gene targets are specifically upregulated in androgen receptor expressing cell types, and that other sex-relevant changes are also initiated in cells lacking androgen receptor expression, through paracrine signaling cascades. We observe a functionally and structurally altered epithelium, shifts in immune populations and directed reduction of capillary vasculature. Finally, we discover evidence of the metabolic impact of androgen and demonstrate how the treatment induces fat loss by specifically targeting adipocyte function. This work provides a comprehensive and mechanistic characterization of the mammary tissue responses to androgen activity at single-cell resolution.
Project description:Type I interferons (IFN-I) are important mediators of antiviral immunity and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females exert an elevated capacity to produce IFN-I in response to activation of toll-like receptor 7 (TLR7) compared to male pDCs, and both hormones and genes encoded by the X chromosome have been implicated in these sex-specific differences. Using longitudinal samples collected from a cohort of trans men receiving testosterone injections as gender-affirming hormone therapy (GAHT), the impact of testosterone on TLR7-mediated IFN-I production by pDCs was assessed. GAHT induced testosterone and estradiol levels within male reference ranges and increased hemoglobin and hematocrit levels, demonstrating biological activity of testosterone. scRNA seq of pDCs showed downregulation of IFN-I-related gene expression signatures, but also revealed inter-donor heterogeneity on the transcriptional level. Longitudinal quantification of IFN-I protein production by pDCs following TLR7-stimulation showed significant and continuous reduction of IFN-I production in trans men, and reduced expression of IFN-I-stimulated genes. These longitudinal studies in trans men demonstrate that testosterone can reduce IFN-I production by pDCs, and provide novel insights into the immune-modulatory role of testosterone in sex differential IFN-I-mediated immune responses.
Project description:Longitudinal DNA methylation profiling of individuals at baseline and 6 and 12 months following Gender Affirming Hormone Therapy (GAHT)
