哈佛大学Fernando D. Camargo小组揭示了HBO1是肝损伤过程中肝细胞可塑性和重编程的表观遗传屏障。相关论文于2025年5月21日发表于国际顶尖学术期刊《细胞—干细胞》杂志上。

该团队定义了单细胞ATAC-seq过程的染色质动力学，并确定YAP/TEAD激活是染色质重塑的关键驱动因素。一项体内CRISPR筛选显示，组蛋白乙酰转移酶HBO1是重编程的关键障碍。HBO1被YAP招募到目标位点，在那里它促进组蛋白H3赖氨酸14乙酰化（H3K14ac），并参与染色质读取器锌指MYND-type containing 8 （ZMYND8）抑制YAP/ TEAD驱动的转录。HBO1的缺失加速了染色质重塑，增强了YAP的结合，并使肝细胞更完整地转变为BEC。他们的发现将HBO1定位为抑制YAP介导的重编程的表观遗传制动，这表明靶向HBO1可能会增强肝细胞的可塑性，从而促进肝脏再生。

据悉，肝损伤过程中肝细胞可重编程为胆道上皮细胞（BECs），但其潜在的表观遗传机制尚不清楚。

附：英文原文

Title: HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury

Author: Wei-Chien Yuan, Andrew S. Earl, Sai Ma, Karel Alcedo, Jacquelyn O. Russell, Fabiana M. Duarte, Yen-Ting Chu, Pei-Chi Chang, Hsin-Yi Chen, Hsin-Hui Chi, Qian Zhu, Alejo E. Rodriguez-Fraticelli, Sachin H. Patel, Yu-Ru Lee, Jason D. Buenrostro, Fernando D. Camargo

Issue&Volume: 2025-05-21

Abstract: Hepatocytes can reprogram into biliary epithelial cells (BECs) during liver injury, but the underlying epigenetic mechanisms remain poorly understood. Here, we define the chromatin dynamics of this process using single-cell ATAC-seq and identify YAP/TEAD activation as a key driver of chromatin remodeling. An in vivo CRISPR screen highlights the histone acetyltransferase HBO1 as a critical barrier to reprogramming. HBO1 is recruited by YAP to target loci, where it promotes histone H3 lysine 14 acetylation (H3K14ac) and engages the chromatin reader zinc-finger MYND-type containing 8 (ZMYND8) to suppress YAP/TEAD-driven transcription. Loss of HBO1 accelerates chromatin remodeling, enhances YAP binding, and enables a more complete hepatocyte-to-BEC transition. Our findings position HBO1 as an epigenetic brake that restrains YAP-mediated reprogramming, suggesting that targeting HBO1 may enhance hepatocyte plasticity for liver regeneration.

DOI: 10.1016/j.stem.2025.04.010

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00177-8