Fig. 8: Transcriptional consequences of ESRRA and H3K18la involved in MASLD/MASH progression.
a Genome-wide distribution of downregulated H3K18la-binding peaks at annotated genomic regions in MASH-ESRRA mouse liver compared with MASH-GFP control by CUT&Tag analysis. b KEGG analysis of the downregulated H3K18la binding peaks at candidate target genes in MASH-ESRRA mouse liver. c Venn diagram depicting 17 downregulated candidate genes with decreased H3K18la modification by integrative analysis of CUT&Tag and RNA-seq data. d Genome browser tracks of CUT&Tag signal at the H3K18la-marked Il18bp, Madd, Gdf15, Cdk1 and Nfe2l2 gene loci. e Heat map depicting 17 candidate genes in c from RNA-seq analysis. f Hepatic mRNA levels of H3K18la-marked genes in MASH mice treated with AAV8-TBG-GFP or AAV8-TBG-ESRRA. n = 6 mice. g Hepatic mRNA expression of H3K18la-marked genes in Esrrafl/fl and EsrraHKO MASH mice. n = 6 mice. h,i H3K18la levels (h) and mRNA expression of H3K18la-marked genes (i) in wild-type primary hepatocytes cultured with 10 mM lactate alone or with C646 treatment (100 μM). j,k Analysis of H3K18la levels (j) and mRNA expression of H3K18la-marked genes (k) in hepatocytes treated with 10 mM lactate after infection with Ad-ESRRA or Ad-GFP. l,m H3K18la levels (l) and mRNA expression of H3K18la-marked genes (m) in Esrrafl/fl and EsrraHKO hepatocytes after treatment with vehicle, 10 mM lactate or 10 mM lactate combined with 100 μM C646. Results were expressed as mean ± s.d. Statistical analysis was performed using a two-tailed Student’s t-test (f, g and k) and two-way ANOVA with Tukey’s post hoc test (i and m). *P < 0.05, **P < 0.01 and ***P < 0.001.
