Single cell multiomics reveals drivers of metabolic dysfunction-associated steatohepatitis

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) has limited treatments, and cell type-specific regulatory networks driving MASLD represent therapeutic avenues. We assayed five transcriptomic and epigenomic modalities in 2.4M cells from 86 livers across MASLD stages. Integrating modalities increased annotation of the genome in liver cell types several-fold over previous catalogs. We identified cell type regulatory networks of MASLD progression, including distinct hepatocyte networks driving MASL and mild and severe fibrosis MASH. Our single cell atlas annotated 88% of MASH-associated loci, including a third affecting hepatocyte regulation which we linked to distal target genes. Finally, we characterized hepatocyte heterogeneity, including MASH-enriched populations with altered repression, localization, and signaling. Overall, our results provide high-resolution maps of liver cell types and revealed novel targets for anti- MASH therapy. Competing Interest Statement K.J.G. has done consulting for Genentech, holds stock in Neurocrine biosciences, and has received honoraria from Pfizer. B.R. is a co-founder of Epigenome Technologies and has equity in Arima Genomics inc. R.M.E. is an employee and shareholder of Pfizer. Funding Statement This work was supported by: Foundation for the NIH (B.R., K.J.G., D.A.B., T.K.) NIH HG011585 (B.R.) NIH HG012059 (B.R., K.J.G) NIH GM008666 (W.E.) NIH T32HL007444 (E.N.F) NIH DK111866 (TK, DAB) NIH DK088837 (TK, DAB) NIH DK099205 (TK, DAB) NIH AA028550 (TK, DAB) NIH DK101737 (TK, DAB) NIH AA011999 (TK, DAB) NIH DK120515 (TK, DAB) NIH AA029019 (TK, DAB) NIH DK091183 (TK, DAB) NIH P42ES010337 (TK, DAB) NIH DK115242 (TK, DAB) NIH CA285997 (DAB) Sanford Stem Cell Fitness and Space Medicine Center at Sanford Stem Cell Institute (TK) Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Deidentified livers - IRB 171883XX, certified by the Human Research Protections Program and Institutional Review Board of the University of California San Diego as not human subjects according to the Code of Federal Regulations, Title 45, part 46 and UCSD Standard Operating Policies and Procedures - from 87 donors were obtained via Lifesharing OPO, which provided the informed consent, laboratory tests (ALT, AST, biochemistry, cell counts, liver biopsy, serology, and others), as well as patient history (cause of death, age, BMI, gender, and underlying diseases, history of alcohol consumption). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes