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

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

doi:10.1016/j.stem.2025.04.010

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

Cell Stem Cell. 2025 Jun 5;32(6):990-1005.e8. doi: 10.1016/j.stem.2025.04.010. Epub 2025 May 21.

Authors

Affiliations

¹ Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan. Electronic address: wcyuan@nycu.edu.tw.
² Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10026 USA.
⁴ Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁵ Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
⁶ Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan.
⁷ Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan.
⁸ Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Lester Sue Smith Breast Center, Department of Molecular and Human Genetics, 1 Baylor Plaza, Houston, TX 77030, USA.
⁹ Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: fernando.camargo@childrens.harvard.edu.

PMID: 40403721
DOI: 10.1016/j.stem.2025.04.010

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.

Keywords: HBO1; Hippo-YAP; epigenetic regulation; hepatocyte reprogramming; in vivo CRISPR screen.

MeSH terms

Acetylation
Adaptor Proteins, Signal Transducing / metabolism
Animals
Cell Plasticity* / genetics
Cellular Reprogramming* / genetics
Chromatin Assembly and Disassembly
Epigenesis, Genetic*
Hepatocytes* / metabolism
Hepatocytes* / pathology
Histone Acetyltransferases* / genetics
Histone Acetyltransferases* / metabolism
Histones / metabolism
Humans
Liver Regeneration
Liver* / injuries
Liver* / metabolism
Liver* / pathology
Mice
Transcription Factors / metabolism
YAP-Signaling Proteins

Substances

Histone Acetyltransferases
YAP-Signaling Proteins
Histones
Yap1 protein, mouse
Adaptor Proteins, Signal Transducing
Transcription Factors