Sterols from cholesterol synthesis control distinct gene regulatory pathways

Sterol intermediates of cholesterol synthesis are largely dedicated to cholesterol. Here we assess how they influence downstream gene regulatory pathways by developing knockouts (KOs) for consecutive enzymes of cholesterol synthesis. Depletion of CYP51 , DHCR24 and SC5D resulted in accumulation of specific sterols. The overlap of deregulated genes was only 9% in terms of steroid metabolism and proliferation control, with majority of pathways changed in just one KO. The CYP51 KO with highly elevated 24,25-dihydrolanosterol showed significantly higher proportion of cells in the G2+M phase, in line with enriched cancer and cell cycle pathways, and elevated LEF1 by activation of WNT/NFKB/SMAD signalling. In contrast, SC5D and DHCR24 KOs (with elevated lathosterol or desmosterol) slowed cell proliferation and promoted apoptosis with downregulated E2F, mitosis, cell cycle transition, and enriched HNF1A tumor suppressor. These findings demonstrate that sterols from cholesterol synthesis control distinct gene regulatory pathways, and only early sterols promote cell proliferation. ### Competing Interest Statement The authors have declared no competing interest. * DEGs : Differentially Expressed Genes FDR : False Discovery Rate GSEA : Gene Set Enrichment Analysis KEGG : Kyoto Encyclopedia of Genes and Genomes LDS : Lipid Depleted Serum MRM : Multiple Reaction Monitoring TF : Transcription Factors WB : Western Blot