ENA0000GenomicsMultiomicsDNA Array Facility, CIG, UNI Lausannehttps://www.ebi.ac.uk/ena/browser/view/PRJNA111369Mus musculusMost metabolic studies are conducted in male animals; thus, the molecular mechanism controlling gender-specific pathways has been neglected, including sex-dependent responses to peroxisome proliferator-activated receptors (PPARs). Here we show that PPARalpha has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and inflammation. In males, this effect is reproduced by the administration of synthetic PPARalpha ligand. Using the steroid hydroxylase gene Cyp7b1 as a model, we elucidated the molecular mechanism of this PPARalpha-dependent repression. Initial sumoylation of the ligand-binding domain of PPARalpha triggers the interaction of PPARalpha with the GA-binding protein alpha bound to the target promoter. Histone deacetylase is then recruited, and histones and adjacent Sp1-binding site are methylated. These events result in the loss of Sp1-stimulated expression, and thus the down-regulation of Cyp7b1. Physiologically, this repression confers protection against estrogen-induced intrahepatic cholestasis, paving the way for a novel therapy against the most common hepatic disease during pregnancy. Keywords: Genetic modification Overall design: Expression profile difference between male and female PPARalpha wild-type and knock-out mice in liver and heart (3 pools of 4 animals in each group). Wild-type (12 males and 12 females) and knock-out PPARalpha SV129 mice (12 males and 12 females) approximately 10 to 12 weeks of age were killed at ZT14 and their livers and hearts quickly removed and frozen.ENA3.4.22.-, vertebrate heart, dorsal tube, Herz, Laboratory, Mus domesticus, mouse, branchial heart, adult heart, mini-ICE, CASP-14, Hearts, Nuclear receptor subfamily 1 group C member 1, House Mouse, jecur, circulatory vessel, chambered heart, House, Mus, AW742785, Mini-ICE, heart, Mus musculus domesticus, cardium, 4933429D07Rik, Mice, cardiac structure., Mus musculus, Nr1c1, Caspase-14 subunit p10, Swiss, heart or heart like organ, mice, Swiss Mouse, iecur, House Mice, Swiss Mice, INSDC_feature:gene, Caspase-14 subunit p19, PPAR-alpha, MICE, Laboratory Mice, domesticus, PPARalpha, sex-specific, Livers, cardiac pump, gender-specific anatomical structure, gender-specific, Mouse, Ppar, Laboratory Mousemouse, mouse <Mus musculus>, house mouse.0.00.00.00.00.00falseMus musculusGender-specific gene repression of PPAR-alpha KO mice in liver and heart2022-05-122014-02-11PRJNA111369GSE143951972983510090