STUDYING THE ROLE OF THE LIVER X RECEPTORS IN THE MAMMARY GLAND DEVELOPMENT: AN IN SILICO APPROACH

OLSZANOWSKI E; RODRIGUEZ SEGUÍ S; PECCI A

Congreso; LXX Reunion Anual de SAIC; 2020

Liver X Receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily, being the oxysterols their endogenous ligands. They play a key role in maintaining the lipid homeostasis by inducing the expression of genes involved in cholesterol transport and the de novo synthesis of triacylglycerides, as well as regulating immune and inflammatory responses. In the mammary gland, these processes are tightly regulated postnatally. During lactation, the gland is endowed with an enormous capacity to synthesize and secrete lipids, however, after weaning, it undergoes a rapid involution in which inflammatory cytokines play a major role. We have previously shown that LXRα is expressed in the lactating murine mammary epithelium and is an important regulator of cholesterol incorporation into the milk (Grinman et. al., 2019), however, little is known about its role in other stages of this organ development. Based on an integrative analysis of public data from previous reports which use technologies such as bulk and scRNA-seq, ChIP-seq and ATAC-seq, we aimed to study at the single cell level in which cell populations of the mammary gland the LXR pathway is more activated. We hypothesized that the activation of the LXR pathway is upregulated from pregnancy to lactation and further downregulated towards involution. Using the genes found to be up- and downregulated upon LXR activation by Boergesen et. al. (2012), we tested if such LXR signature was enriched in the transitions between cell clusters of the scRNA-seq data from Bach et. al. (2017). Preliminary results from our analysis show a significant increase in the expression of the lipogenic Srebf1, Thrsp, Fasn and Me1 genes in mammary epithelial luminal progenitors in the transition from of virgin mice to lactation, and a concomitant decrease of the same set of genes from lactation to post-involution. These results, support the role of the LXR pathway as an important modulator of the lipid homeostasis in the lactating gland, modulating milk requirements to feed the newborn