Youssef, M. K. | bioRxiv Science

bioRxiv2023

DNA methylation sites in early adulthood characterised by pubertal timing and development: A twin study

BackgroundPuberty is a highly heritable and variable trait, with environmental factors having a role in its eventual timing and development. Early and late pubertal onset are both associated with various diseases developing later in life, and epigenetic characterisation of pubertal timing and development could lead to important insights. Blood DNA methylation, reacting to both genotype and environment, has been associated with puberty; however, such studies are relatively scarce. We investigated peripheral blood DNA methylation profiles (using Illumina 450K and EPIC platforms) of 1539 young adult Finnish twins associated with pubertal development scale (PDS) and pubertal age (PA). ResultsFixed effect meta-analysis of the two platforms on 347521 CpGs in common identified 58 CpG sites associated (p < 1 x 10-5) with either PDS or PA. All four CpGs associated with PA and 45 CpGs associated with PDS were sex specific. Thirteen CpGs had a high heritability (h2: 0.51-0.98), while one CpG site (mapped to GET4) had a high shared environmental component accounting for 68% of the overall variance in methylation at the site. Utilising twin discordance analysis, we found 6 CpG sites (5 associated with PDS and 1 with PA) that had an environmentally driven association with puberty. Furthermore, genes with PDS- or PA-associated CpGs were linked to various developmental processes and diseases, such as breast, prostate and ovarian cancer, while methylation quantitative trait loci (meQTLs) of associated CpG sites were enriched in immune pathways developing during puberty. ConclusionsBy identifying puberty-associated DNA methylation sites and examining the effects of sex, environment and genetics, we shed light on the intricate interplay between environment and genetics in the context of puberty. Through our comprehensive analysis, we not only deepen the understanding of the significance of both genetic and environmental factors in the complex processes of puberty and its timing but also gain insights into potential links with disease risks.

genomics↗

bioRxiv2022

Androgen Receptor is a Determinant of Melanoma Targeted Drug Resistance

Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAFV600 mutations regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). However, nearly all relapse within the first two years, and there is a connection between pathways involved in BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. We recently showed that androgen receptor (AR) activity is required for melanoma cell proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells soon after BRAFi exposure. Increased AR expression is by itself sufficient to render melanoma cells BRAFi-resistant, eliciting transcriptional changes of BRAFi resistant subpopulations and elevated EGFR and SERPINE1 expression of likely clinical significance. Inhibition of AR expression and activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, enhances MHC I expression and CD8+ T cells infiltration. Our findings point to targeting AR as a possible co-adjuvant approach for the prevention and management of the disease.

cancer biology↗