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Multi-omics profiling of cholangiocytes reveals chromatin state dynamics during hepatic cystogenesis in polycystic liver disease (ChIP-Seq female)

ABSTRACT: Through genome-wide profiling of chromatin dynamics, we revealed a profound increase of global chromatin accessibility and a switch from H3K9me3 to H3K9ac on cis-regulatory DNA elements of cyst-associated genes during cystogenesis. In an integrated epigenomic and transcriptomic analysis, we identified a transcription factor network associated with dynamic shifts in chromatin states. Functionally, we showed that inhibition of H3K9ac acetyltransferase or H3K9me3 demethylase restored chromatin states and gene expression program to slow cyst growth in PLD mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE237567 | GEO | 2023/07/18

REPOSITORIES: GEO

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Multi-omics profiling of cholangiocytes reveals chromatin state dynamics during hepatic cystogenesis in polycystic liver disease (ChIP-Seq)

Project description:Through genome-wide profiling of chromatin dynamics, we revealed a profound increase of global chromatin accessibility and a switch from H3K9me3 to H3K9ac on cis-regulatory DNA elements of cyst-associated genes during cystogenesis. In an integrated epigenomic and transcriptomic analysis, we identified a transcription factor network associated with dynamic shifts in chromatin states. Functionally, we showed that inhibition of H3K9ac acetyltransferase or H3K9me3 demethylase restored chromatin states and gene expression program to slow cyst growth in PLD mice.

2023-01-27 | GSE202007 | GEO

Multi-omics profiling of cholangiocytes reveals chromatin state dynamics during hepatic cystogenesis in polycystic liver disease (ATAC-Seq)

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Multi-omics profiling of cholangiocytes reveals chromatin state dynamics during hepatic cystogenesis in polycystic liver disease (RNA-Seq Illumina)

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Multi-omics profiling of cholangiocytes reveals chromatin state dynamics during hepatic cystogenesis in polycystic liver disease (RNA-Seq BGI)

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Multi-omics profiling of cholangiocytes reveals chromatin state dynamics during hepatic cystogenesis in polycystic liver disease (RNA-Seq female)

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Multi-omics profiling of cholangiocytes reveals chromatin state dynamics during hepatic cystogenesis in polycystic liver disease (ATAC-Seq female)

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Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

Project description:(1) Background: Polycystic liver disease (PLD) is a heterogeneous group of congenital disorders characterized by bile duct dilatation and cyst development derived from cholangiocytes. Nevertheless, the cystogenesis mechanism is currently unknown and the PLD treatment is limited to liver transplantation. Novel and efficient therapeutic approaches are th6us needed. In this context, the present work has a principal aim to find novel molecular pathways, as well as new therapeutic targets, involved in the hepatic cystogenesis process. (2) Methods: Quantitative proteomics based on SWATH–MS technology were performed comparing hepatic proteomes of Wild Type and mutant/polycystic livers in a polycystic kidney disease (PKD) murine model (Pkd1cond/cond;Tam-Cre−/+). (3) Results: We identified several proteins altered in abundance, with twofold cut-off up-regulation or down-regulation and an adjusted p-value significantly related to hepatic cystogenesis. Then, we performed enrichment and a protein–protein analysis identifying a cluster focused on hepatic fibrinogens. Finally, we validated a selection of targets by RT-qPCR, Western blotting and immunohistochemistry, finding a high correlation with quantitative proteomics data and validating the fibrinogen complex. (4) Conclusions: This work identified a novel molecular pathway in cystic liver disease, highlighting the fibrinogen complex as a possible new therapeutic target for PLD.

2022-04-04 | PXD031253 | Pride

Illumina Human Polycystic Liver Disease and Normal Biliary Stem Cell RNAseq

Project description:Background & aims: Polycystic liver disease (PLD) is an autosomal dominantly inherited disorder caused by mutations in genes such as PRKCSH and SEC63. It has been thought that cysts develop from biliary progenitor cells due to loss-of-heterozygosity (LOH), leading to aberrant proliferation or defects in differentiation. Cyst expansion can be suppressed by somatostatin analogues such as lanreotide. There is no human in vitro model available that truly recapitulates polycystic liver disease. We hypothesize that PLD progenitors can form bipotent liver organoids that carry key features of cyst development. To find gene expression differences between Human Polycystic Liver Disease and Normal Biliary Stem Cells. Methods: Cells from normal biliary duct (n=6), cyst biliary epithelium (n=60) and cyst fluid (n=31) were isolated and placed under conditions suitable for expansion of human adult liver stem cells. We analyzed genetic LOH, gene expression, differentiation capacity, response to lanreotide and cilium formation of these organoids. Results: Cholangiocytes from cyst biliary epithelium (47/60) and cyst fluid (9/31) proved capable of expanding as bipotent liver organoids. Multiple cyst organoids displayed LOH surrounding PRKCSH or SEC63 regions. Organoids formed cilia when proliferation was inhibited. Neither hepatocyte nor biliary differentiation of PLD organoids was impaired. RNAseq revealed no significantly dysregulated pathway in PLD organoids. Lanreotide significantly decreased expansion of liver organoids in comparison to negative control (197% ± 46% versus 547% ± 28%; p: 0.038). Conclusion & discussion: Biliary progenitor cells from patient cyst epithelium and fluid can expand into liver organoids. They recapitulate key characteristics of PLD, and are a promising human in vitro model for research, diagnostics and treatment of polycystic liver diseases and cholangiociliopathies.

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Targeting UBC9-mediated Protein Hyper-SUMOylation in Cystic Cholangiocytes Halts Polycystic Liver Disease in Experimental Models

Project description:Background & Aims: polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Here, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting. Methods: levels and function of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated in vitro, in vivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry. Results: most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdh1-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. In vitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUMO1-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered the proteasome hyperactivity in cystic cholangiocytes, leading to the activation the unfolded protein response (UPR) and stress-related apoptosis.

2020-09-29 | PXD021139 | Pride

Targeting UBC9-mediated Protein Hyper-SUMOylation in Cystic Cholangiocytes Halts Polycystic Liver Disease in Experimental Models

2020-09-29 | PXD021140 | Pride