ArticleHepatology (Baltimore, Md.)2021
Dynamic Transcriptional and Epigenetic Changes Drive Cellular Plasticity in the Liver.
Article in Hepatology (Baltimore, Md.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 44 citations in OpenAlex.
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- Derepression of the epithelial transcription factor GRHL2 promotes direct hepatocyte-to-cholangiocyte transdifferentiation.PLoS biology · 2025Article
- Plastic hepatocyte states limit liver cancer development.Nature communications · 2025Article
- SALL4 Is Required for YAP1-Dependent Malignant and Regenerative Hepatocyte-to-Cholangiocyte Reprogramming.Cancer research communications · 2025Article
- Review
- Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers.Cell genomics · 2025Article
- HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury.Cell stem cell · 2025Article
- Lineage plasticity and reprogramming of epithelial cells during tissue injury and regeneration-lessons from the lineage plasticity of hepatocytes and cholangiocytes induced by liver injury.Regenerative therapy · 2025Review
- In vivo CRISPR screening reveals epigenetic regulators of hepatobiliary plasticity.Genes & development · 2025Article
- Single-cell transcription reveals hepatocyte-to-cholangiocyte reprogramming and biliary gene profile in biliary atresia.Hepatology communications · 2025Article
- Portal Fibrosis and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease and Translational Opportunities.Gastroenterology · 2025Review
- Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application.Signal transduction and targeted therapy · 2024Review
- The yin and yang of pioneer transcription factors: Dual roles in repression and activation.BioEssays : news and reviews in molecular, cellular and developmental biology · 2024Article
- Transdifferentiation occurs without resetting development-specific DNA methylation, a key determinant of full-function cell identity.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Cell competition in primary and metastatic colorectal cancer.Oncogenesis · 2024Review
- Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity.Nature communications · 2024Article
- CD24Cell & bioscience · 2023Article
- Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 as a driver of cell reprogramming.Journal of hepatology · 2023Article
- Evidence for in vitro extensive proliferation of adult hepatocytes and biliary epithelial cells.Stem cell reports · 2023Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
BACKGROUND AND
aimsFollowing liver injury, a fraction of hepatocytes adopt features of biliary epithelial cells (BECs) in a process known as biliary reprogramming. The aim of this study was to elucidate the molecular events accompanying this dramatic shift in cellular identity. APPROACH AND
resultsWe applied the techniques of bulk RNA-sequencing (RNA-seq), single-cell RNA-seq, and assay for transposase-accessible chromatin with high-throughput sequencing to define the epigenetic and transcriptional changes associated with biliary reprogramming. In addition, we examined the role of TGF-β signaling by profiling cells undergoing reprogramming in mice with hepatocyte-specific deletion in the downstream TGF-β signaling component mothers against decapentaplegic homolog 4 (Smad4). Biliary reprogramming followed a stereotyped pattern of altered gene expression consisting of robust induction of biliary genes and weaker repression of hepatocyte genes. These changes in gene expression were accompanied by corresponding modifications at the chromatin level. Although some reprogrammed cells had molecular features of "fully differentiated" BECs, most lacked some biliary characteristics and retained some hepatocyte characteristics. Surprisingly, single-cell analysis of Smad4 mutant mice revealed a dramatic increase in reprogramming.
conclusionHepatocytes undergo widespread chromatin and transcriptional changes during biliary reprogramming, resulting in epigenetic and gene expression profiles that are similar to, but distinct from, native BECs. Reprogramming involves a progressive accumulation of biliary molecular features without discrete intermediates. Paradoxically, canonical TGF-β signaling through Smad4 appears to constrain biliary reprogramming, indicating that TGF-β can either promote or inhibit biliary differentiation depending on which downstream components of the pathway are engaged. This work has implications for the formation of BECs and bile ducts in the adult liver.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.