Oral Presentation 16th Asian Conference on Transcription 2019

Transcriptional Mediator subunit MED23 regulates inflammatory responses and liver fibrosis (933)

Gang Wang 1
  1. Fudan University, Shanghai, SHANGHAI, China

Liver fibrosis, often associated with cirrhosis and hepatocellular carcinomas, is characterized by hepatic damage, an inflammatory response, and hepatic stellate cell (HSC) activation, although the underlying mechanisms are largely unknown. Here, we show that the MED23 subunit of the transcriptional Mediator complex participates in the development of experimental liver fibrosis. Compared with their control littermates, mice with hepatic Med23 deletion exhibited aggravated CCl4-induced liver fibrosis, with enhanced chemokine production and inflammatory infiltration as well as increased hepatocyte regeneration. Mechanistically, the orphan nuclear receptor RORĪ± activates the expression of the liver fibrosis-related chemokines CCL5 and CXCL10, which is suppressed by the Mediator subunit MED23. We further found that the inhibition of Ccl5 and Cxcl10 expression by MED23 likely occurs due to G9a-mediated H3K9 dimethylation of the target promoters. Collectively, these findings reveal hepatic MED23 as a key modulator of chemokine production and inflammatory responses and define the MED23-CCL5/CXCL10 axis as a potential target for clinical intervention in liver fibrosis.