ZNF469 is a novel pro-fibrotic regulator of extracellular matrix in hepatic stellate cells
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ABSTRACT:
PROVIDER: PRJNA1063317 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27483336_1.fastq.gz | Fastqsanger.gz | |||
| SRR27483336_2.fastq.gz | Fastqsanger.gz | |||
| SRR27483337_1.fastq.gz | Fastqsanger.gz | |||
| SRR27483337_2.fastq.gz | Fastqsanger.gz | |||
| SRR27483338_1.fastq.gz | Fastqsanger.gz |
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Project description:Activation of quiescent hepatic stellate cells (HSCs) into proliferative myofibroblasts drives extracellular cellular matrix (ECM) accumulation and liver fibrosis; nevertheless, transcriptional network that promotes such the process remains elusive. ZNF469, a putative C2H2 zinc finger protein, is found to be upregulated upon HSC activation; however, the molecular function of ZNF469 is completely unknown. Here, we show that knockdown of ZNF469 in primary human HSCs impaired proliferation, migration, and collagen production. Conversely, overexpression of ZNF469 in HSCs yielded the opposite results. TGFb promoted expression of ZNF469 in a Smad3-dependent manner where the binding of Smad3 was confirmed at the ZNF469 promoter. RNA-seq data of ZNF469-knockdown HSCs revealed the ECM-receptor interaction as the top affected pathway, and significant downregulation of various collagen and proteoglycan genes was observed. To explore the function of ZNF469, we cloned a full-length open reading frae (ORF) of ZNF469 with an epitope tag and identified a nuclear localization of the protein. ChIP assays revealed the presence of ZNF469 at the promoter of ECM genes, supporting its function as a transcription factor. Analysis of human fibrotic and cirrhotic tissues showed increased expression of ZNF469 and a positive correlation between expression levels of ZNF469 and ECM genes. Moreover, this observation was similar in other fibrotic organs, including heart, lung, and skin. Together, this study is the first to reveal the roles of ZNF469 as a pro-fibrotic factor in HSCs and suggests ZNF469 as a novel target for antifibrotic therapy.
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Project description:O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in hepatic stellate cells
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Project description:O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in hepatic stellate cells (HSCs)
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Project description:Non-alcoholic fatty liver disease (NAFLD)—characterized by excess accumulation of fat in the liver—now affects one third of the world’s population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.
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Project description:Non-alcoholic fatty liver disease (NAFLD)—characterized by excess accumulation of fat in the liver—now affects one third of the world’s population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.
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