Discovery of NAFLD gene regulatory networks with multi-omics (360G-Wellcome-224662_Z_21_Z)

This project will identify the cis-regulatory networks that operate in non- alcoholic fatty liver disease (NAFLD) and characterise their role in hepatocyte lipidomic traits. \- I will carry out single-cell multi-omics in a cohort of liver biopsies representing different stages of NAFLD progression to identify the active genes and corresponding cis-regulatory elements with unprecedented resolution. I will: \- identify the hepatic cell populations that are mostly altered in different degrees of NAFLD and their corresponding marker genes; \- identify the transcription factors that drive the transcriptional/phenotypical changes detected with NAFLD progression; \- pinpoint the hepatic cell populations whose genetic disruption contributes the most to the heritability of NAFLD and/or NAFLD-associated traits. \- To gain mechanistic insights into the contribution of specific genetic loci to NAFLD risk, I will: \- carry out variant level in silico and experimental analyses to prioritise variants likely to be causal; \- use the single-cell multi-omic maps to assign noncoding NAFLD risk variants to target genes in specific hepatic cell populations ('NAFLD genes'); \- perform an unbiased loss-of- function genetic screen to identify 'NAFLD genes' that affect intracellular lipid morphological features in human hepatocytes; \- use gain/loss-of- function models (regulatory variant and gene levels) in human hepatocytes to validate findings and further characterise hits from the genetic screen.