During liver fibrosis, liver sinusoidal endothelial cells (LSECs) release angiocrine signals to recruit inflammatory cells into the liver. P300, a master regulator of gene transcription, is associated with pathological inflammatory response. Therefore, we examined how endothelial p300 regulates angiocrine signaling and inflammation related to portal hypertension and fibrogenesis. Carbon tetrachloride (CCl4 ) or partial inferior vena cava ligation (pIVCL) were used to induce liver injury. Mice with LSEC-specific p300 deletion (p300LSECΔ/Δ ) or C-C motif chemokine ligand 2 (Ccl2) deficiency, NFκB-p50 knockout mice and BRD4 inhibitors in wild-type mice were used to investigate mechanisms of inflammation regulation. Leukocytes were analyzed by mass cytometry by time-of-flight. Epigenetic histone marks were modified by CRISPR-dCas9-KRAB-mediated epigenome-editing. Portal pressure and liver fibrosis were reduced in p300LSECΔ/Δ mice compared to p300fl/fl mice following liver injury. Accumulation of macrophages was also reduced in p300LSECΔ/Δ mouse livers. Ccl2 was the most upregulated chemokine in injured LSECs but its increase was abrogated in p300LSECΔ/Δ mice. While the macrophage accumulation was increased in NFκB-p50 knockout mice with enhanced NFκB activity, it was reduced in mice with LSEC-specific Ccl2 deficiency and mice treated with specific BRD4 inhibitors. In vitro, epigenome-editing of CCL2 enhancer and promoter regions by CRISPR-dCas9-KRAB technology repressed TNFα-induced CCL2 transcription via H3K9 tri-methylation. In contrast, TNFα activated CCL2 transcription by promoting p300 interaction with NFκB and BRD4 leading to H3K27 acetylation at CCL2 enhancer and promoter regions. In summary, endothelial p300 interaction with NFκB and BRD4 increases CCL2 expression, leading to macrophage accumulation, portal hypertension and liver fibrosis. Inhibition of p300 and its binding partners might serve as novel therapies in the treatment of liver diseases. This article is protected by copyright. All rights reserved.