Giuliano, A. E. | bioRxiv Science

bioRxiv2022

TDP 2 modulates the expression of estrogen-responsive oncogenes

With its ligand estrogen, the estrogen receptor (ER) stimulates tumor cell growth by activating a global transcriptional program. This activation involves topoisomerase 2 (TOP2), which resolves topological problems by transiently creating and re-ligating DNA double-strand breaks (DSBs). Recent studies have uncovered the involvement of DNA repair proteins in the repair of TOP2-induced DSBs. These noncanonical repair pathways may serve as backup processes when TOP2 is halted and fails to re-ligate DSBs, but their impact on transcription remains elusive. In this study, we investigated the role of tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme that acts for the removal of halted TOP2 from the 5-end of the DNA, in the estrogen-induced transcriptome. Using TDP2-deficient ER-positive cells and mice, we showed that TDP2 regulates the expression of oncogene MYC. MYC induction by estrogen was a very early event (1 hour) and TOP2-dependent. In TDP2-deficient cells, the induction of MYC by estrogen became prolonged and volatile. Bulk and single-cell RNA-seq identified the oncogenes MYC and CCND1 as genes whose estrogen response was regulated by TDP2. These results suggest that TDP2 may play a role in the repair of TOP2-induced DSBs in specific genomic loci and tightly regulates the expression of oncogenes.

molecular biology↗

bioRxiv2022

The molecular consequences of androgen activity in the human breast

The mammary gland has been extensively studied for estrogen and progesterone reactivity, but the molecular effects of androgen in the breast remain largely unexplored. Transgender men are recorded female at birth but identify as male and may undergo gender-affirming androgen therapy to align their physical characteristics and gender identity. Here we perform single cell resolution transcriptome, chromatin, and spatial profiling of androgen treated breasts from transgender men. We find male-biased androgen receptor gene targets are upregulated in cells expressing androgen receptor, and that paracrine signaling drives sex-relevant changes in other cell types. We observe an altered epithelium, shifts in immune populations, and a reduction of capillary vasculature. Finally, we find evidence of the metabolic impact of androgen and identify a gene regulatory network driving androgen-directed fat loss. This work elucidates the molecular consequences of androgen in the human breast at single cell resolution.

genomics↗