Author:
Elison Weston,Chang Lei,Xie Yang,Miciano Charlene,Yang Qian,Mummey Hannah,Lancione Ryan,Corban Sierra,Sakane Sadatsugu,Lucero Jacinta,Mamde Sainath,Kim Hyun Young,Kim Matthew J,Melton Rebecca,Tucciarone Luca,Lie Audrey,Loe Timothy,Vashist Tanmayi,Dang Kelsey,Elgamal Ruth,Li Daofeng,Vu Melissa,Farah Elie N,Seng Chad,Djulamsah Jovina,Yang Bing,Buchanan Justin,Miller Michael,Tran Mai,Birrueta Janeth Ochoa,Chi Neil C,Wang Ting,D’Antonio-Chronowska Agnieszka,Wang Allen,Kisseleva Tatiana,Brenner David,Ren Bing,Gaulton Kyle J
Abstract
AbstractMetabolic 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.
Publisher
Cold Spring Harbor Laboratory