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A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver injury-associated YAP signaling (ChIP-seq)

ABSTRACT: Following injury, differentiated epithelial cells can serve as a stem cell-independent source for tissue regeneration by undergoing reprogramming into other cell types. The intrinsic molecular basis underlying plasticity of differentiated cells remains largely unaddressed. Here we show that Arid1a, a key component of the SWI/SNF chromatin remodeling complex, controls liver regeneration and gene expression associated with emergence of injury-induced progenitor-like cells (LPLCs). Hepatocyte-specific Arid1a ablation reduces LPLC gene expression in several models of periportal liver injury and impairs liver regeneration, leading to organ dysfunction. Arid1a establishes a permissive chromatin state at LPLC-enriched genes during homeostasis, suggesting it endows hepatocytes with competence to respond to injury-induced signals. Consistently, Arid1a facilitates binding of YAP, a critical regeneration signaling pathway, to LPLC-enriched genes, and Arid1a deletion prevents their YAP-associated induction following injury. Together, these findings provide a framework for studying the contributions of injury-induced LPLCs to periportal liver regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE111500 | GEO | 2019/07/07

REPOSITORIES: GEO

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A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver injury-associated YAP signaling (RNA-seq)

Project description:Following injury, differentiated epithelial cells can serve as a stem cell-independent source for tissue regeneration by undergoing reprogramming into other cell types. The intrinsic molecular basis underlying plasticity of differentiated cells remains largely unaddressed. Here we show that Arid1a, a key component of the SWI/SNF chromatin remodeling complex, controls liver regeneration and gene expression associated with emergence of injury-induced progenitor-like cells (LPLCs). Hepatocyte-specific Arid1a ablation reduces LPLC gene expression in several models of periportal liver injury and impairs liver regeneration, leading to organ dysfunction. Arid1a establishes a permissive chromatin state at LPLC-enriched genes during homeostasis, suggesting it endows hepatocytes with competence to respond to injury-induced signals. Consistently, Arid1a facilitates binding of YAP, a critical regeneration signaling pathway, to LPLC-enriched genes, and Arid1a deletion prevents their YAP-associated induction following injury. Together, these findings provide a framework for studying the contributions of injury-induced LPLCs to periportal liver regeneration.

2019-07-07 | GSE111501 | GEO

A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver injury-associated YAP signaling (ATAC-seq)

2019-07-07 | GSE111499 | GEO

Potential landscape decomposes the cell identity conversion in liver regeneration and tumorigenesis [RNA-seq]

Project description:Tumorigenesis, accompanied by tissue regenerative responses, always occurs during mammalian organ injury. In liver, injury context promotes dedifferentiated liver progenitor-like cells (LPLCs) from hepatocytes for regeneration, and also increases the occurrence of hepatocellular carcinoma (HCC). However, little is known about the contribution of injury specific LPLCs to tumorigenesis. Here, by using lineage tracing model, we have demonstrated that LPLCs are highly susceptible to oncogene-induced tumorigenesis. By using quantitative landscape of differentiation dynamics (LDD) model, we have constructed potential landscape of liver regeneration and tumorigenesis via scRNA-seq data, in order to predict distinct regulations of cell fate decisions. Applying this landscape with in vivo validation by transgenic mouse model, we have found blocking Wnt activation not only inhibits tumorigenesis, but also decreases LPLCs. Surprisingly, by using least action pathway analysis, we have decomposed regeneration and tumorigenesis routes, and found EP300 is specifically involved in tumorigenesis, which is further supported by in vivo EP300-knockout model and EP300 inhibitor assays. These findings might be applied as a framework to find tumor-specific regulators and develop strategies specifically inhibiting tumor initiation while leaving tissue regeneration unaffected.

2024-09-29 | GSE244910 | GEO

Potential landscape decomposes the cell identity conversion in liver regeneration and tumorigenesis [ChIP-seq]

2024-09-29 | GSE244909 | GEO

Potential landscape decomposes the cell identity conversion in liver regeneration and tumorigenesis [scRNA-seq]

2024-09-29 | GSE244911 | GEO

Macrophages trigger injury-induced hepatocyte reprogramming via IL-6/gp130/STAT3 axis [ChIP-Seq]

Project description:The liver is a pivotal organ possessing remarkable regenerative capacity. By employing murine liver injury models and lineage tracing strategy, recent studies have demonstrated that differentiated hepatocytes undergo reprogramming to SOX9+HNF4α+ liver progenitor-like cells (LPLCs), and serve as a totally new cell source for mammalian liver regeneration. However, it is largely unknown how hepatocyte reprogramming is regulated. In this study, we focus on analyzing the microenvironment cues in triggering hepatocyte reprogramming in liver injuries. By performing single-cell RNA sequencing (scRNA-seq) of hepatocyte reprogramming in liver injury, we find immune response is significantly activated. Notably, by lineage depletion, macrophages, especially kupffer cells, but not T cells, B cells, natural killer cells or neutrophils, are found essential for hepatocyte reprogramming and liver regeneration. IL-6, derived specifically from activated kupffer cells, triggers hepatocyte reprogramming via gp130/STAT3 signaling. Furthermore, STAT3 triggers gene expression by binding to Arid1a-dependent pre-opened regeneration-responsive enhancers (RREs) of reprogramming genes. Collectively, this study provides key insights into kupffer cells/IL-6/STAT3-mediated hepatocyte reprogramming and liver regeneration, which may serve as the base for new therapeutic strategies in facilitating endogenous repair mechanisms.

2022-08-24 | GSE193848 | GEO

Macrophages trigger injury-induced hepatocyte reprogramming via IL-6/gp130/STAT3 axis [RNA-Seq]

2022-08-24 | GSE193849 | GEO

ChIP-seq analysis of E2f4, H3K4me2 and H3K27ac in the mouse livers

Project description:Arid1a is the subunit of SWI/SNF complex, which was reported to guide SWI/SNF to DNA. Here, we found that loss of Arid1a in the liver results in improved liver regeneration after partial hepatectomy.Genome-wide analysis showed that after hepatectomy,loss of Arid1a reduces the recruitment and activity of E2F4 on target promoters, resulting in expression programs that favor regeneration during injury. Correspondingly, these promoters showed increased H3k4me2 and H3k27ac marks, indicating de-repression of these E2f target genes. The post partial hepatectomy mice liver cells were fixed and isolated, analysis of genomic occupancy of E2f4,H3K4me2,H3K27ac in hepatocytes from Arid1a WT and Arid1a liver specific KO mice by ChIP-seq.

2016-03-30 | E-GEOD-76927 | biostudies-arrayexpress

ChIP-seq analysis of Arid1a and C/ebpÎ± in the mouse livers

Project description:Arid1a is the subunit of SWI/SNF complex, which was reported to guide SWI/SNF to DNA. Here, we found that loss of Arid1a in the liver and other adult tissues results in improved organ regeneration. Within SWI/SNF complexes, Arid1a physically interacts with C/ebpÎ±, a hepatocyte transcription factor that drives maturation and limits proliferation. Genome-wide analysis showed that loss of Arid1a reduces the recruitment and activity of C/ebpÎ± on target promoters, resulting in expression programs that favor regeneration and cellular fitness during injury. Arid1a binding is enriched in promoters near transcriptional start sites (TSSs), and C/ebpÎ± binds at precisely the same positions, indicating that Arid1a facilitates C/ebpÎ± binding across the genome. Perfuse and isolate primary hepatocytes from mice livers, analysis of genomic occupancy of C/ebpÎ± and H3K4me2 in hepatocytes from Arid1a WT and Arid1a liver specific KO mice by ChIP-seq. Analysis of genomic occupancy of Arid1a in the hepatocytes from V5-Arid1a transgenic mouse by ChIP-seq.

2016-03-30 | E-GEOD-65167 | biostudies-arrayexpress

Regeneration Defects in Livers of Mice With Mutations in Yap and Taz Caused by Bile Duct Disruption and Cholestasis

Project description:Background and aims: The Hippo pathway and its downstream effectors YAP and TAZ (YAP/TAZ) are heralded as important regulators of organ growth and regeneration. However, different studies provided contradictory conclusions about their role during regeneration of different organs ranging from promoting proliferation to inhibiting it. Here, we resolve the function of YAP/TAZ during regeneration of the liver, where Hippo’s role in growth control has been studied most intensely. Methods: We evaluated liver regeneration after CCl4 toxic liver injury in mice with conditional deletion of Yap/Taz in hepatocytes and/or biliary epithelial cells and measured the behavior of different cell types during regeneration by histology, RNA-sequencing and flow cytometry. Results: We found that YAP/TAZ were activated in hepatocytes in response to CCl4 toxic injury. However, their targeted deletion in adult hepatocytes did not noticeably impair liver regeneration. In contrast, Yap/Taz deletion in adult bile ducts caused severe defects and delay in liver regeneration. Mechanistically, we show that Yap/Taz mutant bile ducts degenerated, causing cholestasis which stalled the recruitment of phagocytic macrophages and the removal of cellular corpses from injury sites. Elevated bile acids activated PXR, which was sufficient to recapitulate the phenotype observed in mutant mice. Conclusions: Our data show that YAP/TAZ are practically dispensable in hepatocytes for liver development and regeneration. Rather, YAP/TAZ play an indirect role in liver regeneration by preserving bile duct integrity and securing immune cell recruitment and function.

2020-11-02 | GSE157088 | GEO

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