A Homeostatic Arid1a-Dependent Permissive Chromatin State Licenses Hepatocyte Responsiveness to Liver-Injury-Associated YAP Signaling

Li, Weiping; Yang, Liguang; He, Qiang; Hu, Chaobo; Zhu, Linying; Ma, Xiaolong; Ma, Xueyan; Bao, Shujie; Lu, Liwei; Chen, Yingying; Deng, Xiangbing; Zhang, Xin; Cen, Jin; Zhang, Lei; Wang, Zhong; Xie, Wei‐Fen; Li, Hong; Li, Yixue; Hui, Lijian

doi:10.1016/j.stem.2019.06.008

Cited by 94 publications

(96 citation statements)

References 66 publications

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“…When cultured in vitro, both LPLCs and their duct cell-like progeny were capable of selfrenewal [28,29], further supporting the progenitor proprieties of these LPLCs. Notably, hepatocyte to LPLC dedifferentiation was not induced in pericentral liver injury [30]. Other studies have shown the contribution of biliary epithelial cell-derived oval cells to hepatocyte regeneration, mainly through labeling Foxl1 + and Lgr5 + cells during liver injury [32,33].…”

Section: Trends In Cell Biologymentioning

confidence: 86%

“…were found to dedifferentiate into liver progenitor-like cells (LPLCs), expressing both hepatocyte and biliary epithelial cell markers, particularly SOX9, a putative LPC marker [27][28][29]. Remarkably, hepatocyte-derived LPLCs contributed to nearly 20% of newly regenerated hepatocytes in vivo [30]. Moreover, the LPLCs generated duct-like cells when liver injury was prolonged [27,29,31].…”

Section: Trends In Cell Biologymentioning

confidence: 99%

“…During hepatocyte to LPLC conversion, several signaling pathways, including Notch [44], Wnt [45], and the Hippo pathway [46], have been found to regulate hepatocyte to LPLC dedifferentiation. Hepatocyte-specific overexpression of NICD, a constitutively active form of Notch1, or Yap was sufficient to induce hepatocyte dedifferentiation in normal livers [44,46], whereas injury-induced hepatocyte dedifferentiation was blocked on NICD or Yap deletion in hepatocytes [30,44]. Because the Notch pathway is a functional effector downstream of the Hippo pathway, it is possible that the Hippo pathway regulates hepatocyte dedifferentiation through the modulation of Notch signaling [46].…”

Section: Mechanisms Regulating Hepatocyte Plasticitymentioning

confidence: 99%

“…In additional to signaling pathways that regulate hepatocyte dedifferentiation, a recent study identified a role for chromatin accessibility in hepatocyte dedifferentiation. Arid1a, a key component of the SWI/SNF chromatin remodeling complex, endowed hepatocytes with the ability to respond to injury-induced Yap signals [30]. Arid1a-deficient hepatocytes were functionally normal under normal physiological conditions; however, they lost the ability to be reprogrammed into LPLCs during periportal injury.…”

Section: Mechanisms Regulating Hepatocyte Plasticitymentioning

confidence: 99%

“…Arid1a-deficient hepatocytes were functionally normal under normal physiological conditions; however, they lost the ability to be reprogrammed into LPLCs during periportal injury. Mechanistically, Arid1a has been found to establish a transcriptionally permissive chromatin state at the sites of LPLC-enriched genes in normal hepatocytes, thereby facilitating Yap in the transcriptional activation of LPLC genes to initiate hepatocyte dedifferentiation [30]. Depletion of Arid1a caused the chromatin in LPLC-enriched genes to be less accessible, with the result that Yap-induced expression of these LPLC-enriched genes was markedly impaired [30].…”

Section: Mechanisms Regulating Hepatocyte Plasticitymentioning

confidence: 99%

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Cell Plasticity in Liver Regeneration

Hui

2020

Trends in Cell Biology

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104

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The liver, whose major functional cell type is the hepatocyte, is a peculiar organ with remarkable regenerative capacity. The widely held notion that hepatic progenitor cells contribute to injury-induced liver regeneration has long been debated. However, multiple lines of evidence suggest that the plasticity of differentiated cells is a major mechanism for the cell source in injury-induced liver regeneration. Investigating cell plasticity could potentially expand our understanding of liver physiology and facilitate the development of new therapies for liver diseases. In this review, we summarize the cell sources for hepatocyte regeneration and the clinical relevance of cell plasticity for human liver diseases. We focus on mechanistic insights on the injury-induced cell plasticity of hepatocytes and biliary epithelial cells and discuss future directions for investigation. Specifically, we propose the notion of 'reprogramming competence' to explain the plasticity of differentiated hepatocytes. Liver Regeneration and Cell PlasticityThe liver harbors remarkable regenerative capacity and performs multiple physiological functions [1,2]. However, as this organ is central for metabolism and detoxification, it often suffers extraneous injury and gradually loses its regenerative ability [1,2]. Understanding the mechanisms of liver regeneration is a fundamental topic in liver biology. Since hepatocytes are the primary effector cells for liver physiological functions, the cell source for new hepatocytes after injury has been a main focus in liver regeneration research. It has long been debated whether stem cells contribute to injury-induced liver regeneration. However, recent studies have shown that cell sources other than stem cells also contribute to injury-induced liver regeneration [3]. Cell reprogrammingthat is, the plasticity of hepatocytes and biliary epithelial cellshas been identified as a major pathway to generate new hepatocytes in response to liver injury. Therefore, a better understanding of the underlying mechanisms of injury-induced cell plasticity in vivo may facilitate the development of cell-plasticitybased therapies. In this review, we summarize the latest findings on cell sources with mechanistic regulation in liver regeneration and discuss their clinical relevance to human liver diseases. Liver Homeostasis under Physiological ConditionsIt has long been proposed that the liver harbors liver progenitor cells (LPCs) in the canal of Hering, a structure that connects bile canaliculi with bile ducts in periportal areas, to fulfil liver regeneration requirements under normal physiological conditions [2]. LPCs are characterized based on the following properties: (i) clonogenic ability with high proliferation potential; (ii) the ability to differentiate into both hepatocytes and cholangiocytes under culture conditions; and (iii) liver repopulation ability after transplantation [2]. The 'streaming liver' model was proposed decades ago to describe the contribution of LPCs to in vivo liver homeostasis. This model de...

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Section: Trends In Cell Biologymentioning

confidence: 86%

Section: Trends In Cell Biologymentioning

confidence: 99%

Section: Mechanisms Regulating Hepatocyte Plasticitymentioning

confidence: 99%

Section: Mechanisms Regulating Hepatocyte Plasticitymentioning

confidence: 99%

Section: Mechanisms Regulating Hepatocyte Plasticitymentioning

confidence: 99%

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Cell Plasticity in Liver Regeneration

Hui

2020

Trends in Cell Biology

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104

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Paraspeckle Protein NONO Promotes TAZ Phase Separation in the Nucleus to Drive the Oncogenic Transcriptional Program

et al. 2021

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The Hippo pathway effector TAZ promotes cellular growth, survival, and stemness through regulating gene transcription. Recent studies suggest that TAZ liquid-liquid phase separation (LLPS) compartmentalizes key cofactors to activate transcription. However, how TAZ LLPS is achieved remains unknown. Here, it is shown that the paraspeckle protein NONO is required for TAZ LLPS and activation in the nucleus. NONO is a TAZ-binding protein. Their interaction shows temporal regulation parallel to the interaction between TAZ and TEAD as well as to the expression of TAZ target genes. NONO depletion reduces nuclear TAZ LLPS, while ectopic NONO expression promotes the LLPS. Accordingly, NONO depletion reduces TAZ interactions with TEAD, Rpb1, and enhancers. In glioblastoma, expressions of NONO and TAZ are both upregulated and predict poor prognosis. Silencing NONO expression in an orthotopic glioblastoma mouse model inhibits TAZ-driven tumorigenesis. Together, this study suggests that NONO is a nuclear factor that promotes TAZ LLPS and TAZ-driven oncogenic transcriptional program.

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Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF‐α signaling

Qi,

Lu,

et al. 2023

Cancer Communications

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BackgroundHepatic inflammation is the major risk factor of hepatocellular carcinoma (HCC). However, the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood. This study was designed to investigate the role of ETS translocation variant 4 (ETV4) in linking hepatic inflammation to HCC.MethodsQuantitative real‐time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines. RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4. Hepatocyte‐specific ETV4‐knockout (ETV4fl/fl, alb‐cre) and transgenic (ETV4Hep‐TG) mice and diethylnitrosamine‐carbon tetrachloride (DEN‐CCL4) treatment experiments were applied to investigate the function of ETV4 in vivo. The Cancer Genome Atlas (TCGA) database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor‐alpha (TNF‐α) and mitogen‐activated protein kinase 11 (MAPK11).ResultsWe revealed that ETV4 was highly expressed in HCC. High levels of ETV4 predicted a poor survival rate of HCC patients. Then we identified ETV4 as a transcription activator of TNF‐α and MAPK11. ETV4 was positively correlated with TNF‐α and MAPK11 in HCC patients. As expected, an increase in hepatic TNF‐α secretion and macrophage accumulation were observed in the livers of ETV4Hep‐TG mice. The protein levels of TNF‐α, MAPK11, and CD68 were significantly higher in the livers of ETV4Hep‐TG mice compared with wild type mice but lower in ETV4fl/fl, alb‐cre mice compared with ETV4fl/fl mice as treated with DEN‐CCL4, indicating that ETV4 functioned as a driver of TNF‐α/MAPK11 expression and macrophage accumulation during hepatic inflammation. Hepatocyte‐specific knockout of ETV4 significantly prevented development of DEN‐CCL4‐induced HCC, while transgenic expression of ETV4 promoted growth of HCC.ConclusionsETV4 promoted hepatic inflammation and HCC by activating transcription of TNF‐α and MAPK11. Both the ETV4/TNF‐α and ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC. ETV4+TNF‐α were potential prognostic markers for HCC patients.

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A Homeostatic Arid1a-Dependent Permissive Chromatin State Licenses Hepatocyte Responsiveness to Liver-Injury-Associated YAP Signaling

Abstract: Highlights d Arid1a expression in hepatocytes promotes liver regeneration after periportal injuries d Arid1a endows a permissive chromatin state to liverprogenitor-like cell-enriched genes d Arid1a-dependent permissive chromatin defines responsiveness to regenerative signals

Cited by 94 publications

References 66 publications

Cell Plasticity in Liver Regeneration

Cell Plasticity in Liver Regeneration

Paraspeckle Protein NONO Promotes TAZ Phase Separation in the Nucleus to Drive the Oncogenic Transcriptional Program

Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF‐α signaling

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