Super-enhancer signature reveals key mechanisms associated with resistance to non-alcoholic steatohepatitis in humans with obesity

Abstract

Non-alcoholic fatty liver disease (NAFLD), which often co-occurs with obesity and type 2 diabetes, is the most common cause of chronic liver disease worldwide. A subset of patients with NAFLD progress to the severe form known as non-alcoholic steatohepatitis (NASH), which increases the risk of developing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. The molecular underpinnings of the progression from NAFLD to NASH in patients is poorly understood. Active enhancer landscapes are known to determine cell states and can point to key transcription factors (TF), genes, and pathways in disease pathogenesis or resistance. Also, while super-enhancers have helped reveal key disease drivers in several cancer types, they remain undefined in NASH. To define the enhancer signature of NASH-prone (NP) and NASH-resistant (NR) phenotypes in humans, we performed chromatin run-on sequencing (ChRO-seq) analysis on liver biopsies of individuals with severe obesity who were stratified into either the NP or NR group. We defined the active enhancer signature, super-enhancer linked genes, and the candidate TF networks in human NP and NR livers. Notably, we showed that NR-activated genes that are linked to NR-specific enhancers/super-enhancers are involved in serine and glycine biosynthesis (SHMT, BHMT) as well as glycine utilization (GLYAT, GATM). Overall, this study has defined for the first time the active enhancer/super-enhancer landscape and the underlying TF programs of NASH resistance in humans with obesity.

Alterations in the hepatocyte epigenetic landscape in steatosis

“…NFIL3 and JUNB have been reported to play a role in all stages of human NAFLD [43]. NFIL3 was described as part of an enhancer hotspot associated gene in NASH-prone livers [44] and mechanistically affects gluconeogenesis in hepatocytes [45, p. 3] and lipid accumulation [46]. The preference of JunB in for ECM cluster genes (cluster 2) con rmed a recently described positive correlation of JunB levels with liver brosis in human and murine samples [47].…”

Alterations in the hepatocyte epigenetic landscape in steatosis

“…NFIL3 and JUNB have been reported to play a role in all stages of human NAFLD [ 46 ]. NFIL3 was described as part of an enhancer hotspot associated gene in NASH-prone livers [ 47 ] and mechanistically affects gluconeogenesis in hepatocytes [ 48 , p. 3] and lipid accumulation [ 49 ]. The preference of JunB for ECM cluster genes ( cluster 2) confirmed a recently described positive correlation of JunB levels with liver fibrosis in human and murine samples in hepatic stellate cells [ 50 ].…”