Epigenetically controlled endothelial promyelocytic leukemia drives liver inflammation and fibrosis - PubMed
6 hours ago
- #Liver Fibrosis
- #Epigenetics
- #Inflammation
- Epigenetically aberrant liver sinusoidal endothelial cells (LSECs) drive liver inflammation and fibrosis.
- BRD4-dependent super-enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML).
- PML binds BRD4, amplifying proinflammatory signaling via PML/BRD4 condensate formation through phase separation.
- LSEC-specific depletion of the PML/BRD4 complex reduces liver inflammation and fibrosis in mice.
- Single-cell RNA-sequencing shows reprogrammed proinflammatory angiocrine landscape in LSECs during fibrosis.
- TIMP1+ LSECs recruit CD63+ monocyte-derived macrophages (MoMFs), promoting fibrosis progression.
- Pharmacological BRD4 inhibition or PML-SE repression alleviates liver inflammation and fibrosis.