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In vivo CRISPR screen reveals interplay of epigenetic regulators underlies kinetics of hepatobiliary reprogramming [CUT&Tag]

ABSTRACT: Under chronic liver injury, a small fraction of hepatocytes undergoes reprogramming to biliary epithelial cells (BECs) through a multistep process of chromatin and transcriptional remodeling in which the hepatocyte phenotype is repressed and the biliary phenotype is activated. However, the epigenetic basis underlying this phenomenon is largely unknown. Here, using a lineage-traced model of cholestatic liver injury, we investigated the role of histone posttranslational modification in the kinetics of biliary reprogramming. In this study, we performed CUT&Tag to profile the changes in histone landscape throughout reprogramming and explored the impact of Nsd1 and Kdm2a knockout.

ORGANISM(S): Mus musculus

PROVIDER: GSE270508 | GEO | 2025/01/01

REPOSITORIES: GEO

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In vivo CRISPR screen reveals interplay of epigenetic regulators underlies kinetics of hepatobiliary reprogramming [RNA-Seq]

Project description:Under chronic liver injury, a small fraction of hepatocytes undergoes reprogramming to biliary epithelial cells (BECs) through a multistep process of chromatin and transcriptional remodeling in which the hepatocyte phenotype is repressed and the biliary phenotype is activated. However, the epigenetic basis underlying this phenomenon is largely unknown. Here, we profiled cells after knockout of Nsd1 or Kdm2a at two reprogramming stages to assess the transcriptional differences imposed by epigenetic dysregulation.

2025-01-01 | GSE270509 | GEO

RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis

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2020-08-27 | GSE156894 | GEO

Profiling histone post-translational modifications in mouse adult hepatocytes, biliary epithelial cells and biliary reprogrammed cells from hepatocytes.

Project description:Recent studies have demonstrated that hepatocytes can be reprogrammed into biliary epithelial cell-like cells under cholestatic liver injury. To investigate the changes in histone post-translational modification in hepatocyte-derived reprogramming cells, we performed Cleavage Under Targets and Tagmentation (CUT&Tag)-sequencing.

2024-01-31 | GSE237908 | GEO

VEGFA mRNA-LNP promote biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis

Project description:The goal of this experiment was to analyse transcriptomic changes between Biliary epithelial cells or BECs from the liver of mice treated with Acetaminophen (a drug that causes acute liver injury) in combination with AAV8-Tbg-p21 viral vector to induce hepatocyte senecence. The aim was to understand the impact of injury on transcriptional status of biliary epithelial cells. Briefly, we analyzed mouse liver cells (hepatocytes and non-parenchymal cells fractions) obtained by in-situ liver perfusion 48 h after injury. We further extracted cells corresponding to the hepatocyte and biliary epithelial cell gene signature for detailed analysis. Two separate clusters of BECs (BEC1 and BEC2) were further identified and analyzed to study their transcriptional changes and corresponding pathways.

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Single cell analysis of human fetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors

Project description:The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin of human liver parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report the existence of a hepatobiliary hybrid progenitor (HHyP) population in human fetal liver using single-cell RNA sequencing. HHyPs are anatomically restricted to the ductal plate of fetal liver and maintain a unique transcriptional profile distinct from fetal hepatocytes, mature hepatocytes and mature BECs. In addition, molecular heterogenicity within the EpCAM+ population of freshly isolated fetal and adult human liver reveals diverse gene expression signatures of hepatic and biliary lineage potential. Finally, we FACS isolated fetal HHyPs and confirmed their hybrid progenitor phenotype in vivo. Our study suggests that hepatobiliary progenitor cells previously identified in mice also exist in humans, and can be distinguished from other parenchymal populations, including mature BECs, by distinct gene expression profiles.

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Prominin-1-expressing Hepatic Progenitor Cells Induce Fibrogenesis in Murine Cholestatic Liver Injury

Project description:Purpose: Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin-1 (Prom1/CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1-expressing HPCs promote fibrogenesis in cholestatic liver injury. Methods: Using Prom1CreERT2-nLacZ/+;Rosa26Lsl-GFP/+ mice, we traced the fate of Prom1-expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Results: Prom1-expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential towards both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1-expressing HPCs gave rise to both PROM1(+) and PROM1(-) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA-sequencing analysis of GFP(+) Prom1-expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor-b pathway activation. Conclusion: Our data indicate that Prom1-expressing HPCs promote biliary fibrosis by activation of myofibroblasts in cholestatic liver injury.

2020-06-30 | GSE144726 | GEO

RNA-seq on biliary epithelial cells (BECs) of Klf5 LKO mice upon DDC injury

Project description:In other to assess functional involvement of Klf5 in DR regulation, we made liver-specific Klf5 knockout mice. Ductular reaction upon cholestatic liver injury is severely suppressed in these mice. We conducted RNA-seq analysis on the BECs from control mice and Klf5 LKO mice upon DDC injury to further elucidate the Klf5 functions.

2018-03-16 | GSE97167 | GEO

Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration

Project description:Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration The liver is an essential organ with compartmentalized metabolic processes and significant regenerative capabilities. Repopulation of the liver parenchyma can transpire from both main epithelial cell types, hepatocytes and biliary epithelial cells (BECs). Here, we harness high-throughput single-cell RNA sequencing (scRNA-seq) to dissect the transcriptional heterogeneity and cellular diversity of these epithelial compartments in homeostasis and injury. Our data argue against the idea of a rigidly defined liver progenitor cell in BECs, finding instead that heterogeneity in homeostatic BECs is principally distinguished by a YAP-dependent program that defines a dynamic cellular state. We report that this cellular state dynamically fluctuates between BECs and can be induced in the majority of BECs in response to environmental stimuli and injury. Functional studies demonstrate that YAP is distinctly required for BEC survival in homeostasis, uncovering a tight physiological necessity for YAP signaling in BECs compared to other tissues. YAP is also essential for hepatocyte reprogramming towards a ductal progenitor fate upon injury. Finally, our data demonstrate that this YAP-driven cellular state is highly responsive to injury by physiological exposure to bile acids (BAs) via apical sodium-bile acid transporter, and that sequestration of endogenous BAs rescues the cell loss phenotype associated with homeostatic Yap deletion. Together, our findings uncover previously undescribed molecular heterogeneity within the ductal epithelium and highlight a distinct and potent role for YAP as a protective rheostat and regenerative regulator in the mammalian liver.

2019-05-08 | GSE125688 | GEO

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