Fig. 7

Hemin-induced gene expression profiling in mouse primary hepatocytes. A Eight-week-old C57BL/6 mice were injected with the recombinant AAV8-shNC or AAV8-shHmox1 through tail vein injection. The mice were monitored with the serum alanine aminotransferase (ALT), and the mice with increased ALT levels were euthanized for further examinations. B Serum ALT levels of mice before they were euthanized for liver dissection. Hmox1 knockdown induced serum ALT elevation, which indicated liver damage. C Hematoxylin and eosin (H&E) staining of the dissected liver tissues showing pathological changes in Hmox1 knockdown mice. D Workflow for isolation and culture of mouse primary hepatocytes [69, 70]. E MA plot showing gene expression changes in mouse primary hepatocytes in response to hemin treatment for 6 h. F,G Network enrichment analysis of upregulated (F) and downregulated (G) genes by hemin treatment. Each cluster is represented by different colors and each enriched term is represented by a circle node. H Proposed model depicting two ways for hemin to participate in gene transcription regulation. In the BACH1-NRF2-dependent activation pathway, hemin induces degradation of BACH1 and binding of NRF2 to enhancer regions, which activates the transcription of target genes, including HMOX1 and FTH1. In this study, we present a G4-dependent model for metabolic regulation of gene expression and chromatin landscapes by porphyrin metabolites. G4 works as a hemin sensor and could be stabilized by hemin. Hemin-induced G4 stabilization hampers the loading of Pol II, TFIIB, COMPASS, and P300, leading to the impairment of transcription initiation of target genes and the alteration of chromatin modifications