Fig. 4.

RORγ plays a dominant role over SREBP2 to reprogram cholesterol biosynthesis. a Venn diagram of the number of high-confidence (FDR 1% and IDR 1%) binding sites shared by RORγ ChIP-seq and SREBP2 ChIP-seq in HCC70 cells. FDR false-discovery rate, IDR irreproducible discovery rate. b Gene ontology analysis of genes that displayed ChIP-seq peaks for both RORγ and SREBP2 in HCC70 cells. Gene list of each program is shown in Supplementary Table 1. Hypergeometric and binomial test p value. c Transcription factor (TF) motifs that are enriched in chromatin regions with SREBP2 peaks diminished by 2.5 µM XY018 treatment of HCC70 for 24 h. d ChIP-seq profiles (left) and heat maps of ChIP-Seq signal intensity (right) of SREBP2, RORγ, or H3K27ac within ±3-kb windows around the center of peak regions in HCC70 cells treated with 2.5 µM XY018 or vehicle for 24 h. e ChIP-Seq profiles of SREBP2 (top), RORγ (middle), or H3K27ac (bottom) binding within ±3-kb windows around the center of peak regions on genes involved in cholesterol-biosynthesis pathway in HCC70 cells treated as in (d). f ChIP-seq signal visualization of SREBP2 (top), RORγ (middle), or H3K27ac (bottom) at representative cholesterol-biosynthesis genes SQLE and DHCR24 in HCC70 cells treated as in (d). g MVK (wild type or RORE mutated) promoter luciferase reporter activity changes by RORγ overexpression or treatment with 2.5 µM RORγ antagonists XY018 and GSK805 in MDA-MB468 cells for 24 h. Data are shown as mean ± s.d. n = 6. Student’s t test. ^∗∗p < 0.01. h MVK promoter luciferase reporter activity changes in HEK293T cells co-transfected with RORC, nSREBP2, or both for 24 h. n = 6. Data are shown as mean ± s.d. Student’s t test. ^∗∗p < 0.01. i Co-IP analysis with V5-RORC expressing MDA-MB468 cells transfected with Flag-nSREBP2 expression vector. Twenty-four hours after transfection, cells were treated with 2.5 µM XY018 or vehicle for another 24 h. The nuclear extracts were used for co-IP with indicated antibodies. The experiments were repeated three times. Source data are provided in a Source Data file