Plagl1/Zac1 regulates extracellular matrix genes and the imprinted gene network
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE99409 | GEO | 2017/11/24
SECONDARY ACCESSION(S): PRJNA388408
REPOSITORIES: GEO
Similar Datasets
Project description:In order to determine the imprinted transcription factor Zac1 targets, we overexpressed Zac1 in a mouse insulinoma cell line and measured the regulated expressed genes by RNA-seq. We have shown that Zac1 regulates many genes belonging to the Imprinted Gene Network, including genes coding for the extra-cellular matrix.
2017-11-24 | GSE84914 | GEO
Project description:In order to determine the imprinted transcription factor Zac1 targets, we overexpressed Zac1 in a neuroblastoma cell line and measured both the regulated expressed genes by Differential Gene Expressed analysis and Zac1 binding sites throughout the mouse genome by ChIP-seq. We have shown that Zac1 regulates and binds closed to many genes belonging to the Imprinted Gene Network.
2017-11-24 | GSE75942 | GEO
Project description:In order to determine the imprinted transcription factor Zac1 targets, we overexpressed Zac1 in a neuroblastoma cell line and measured both the regulated expressed genes by Differential Gene Expressed analysis and Zac1 binding sites throughout the mouse genome by ChIP-seq. We have shown that Zac1 regulates and binds closed to many genes belonging to the Imprinted Gene Network.
2017-11-24 | GSE75943 | GEO
Project description:Background and Aims Within the next decade, non-alcoholic fatty liver disease (NAFLD) is predicted to become the most prevalent cause of childhood liver failure in developed countries. Predisposition to juvenile NAFLD can be programmed during early life in response to maternal metabolic syndrome (MetS), but the underlying mechanisms are poorly understood. We hypothesized that imprinted genes, defined by expression from a single parental allele, play a key role in maternal MetS-induced NAFLD, due to their susceptibility to environmental stressors and their functions in liver homeostasis. We aimed to test this hypothesis and determine the critical periods of susceptibility to maternal MetS. Approach and Results We established a mouse model to compare the effects of MetS during prenatal and postnatal development on NAFLD. Postnatal but not prenatal MetS exposure is associated with histological, biochemical and molecular signatures of hepatic steatosis and fibrosis in juvenile mice. Using RNA-seq, we show that the Imprinted Gene Network (IGN), including its regulator Zac1, is up-regulated and over-represented among differentially expressed genes, consistent with a role in maternal MetS-induced NAFLD. In support of this, activation of the IGN in cultured hepatoma cells by over-expressing Zac1 is sufficient to induce signatures of profibrogenic transformation. Using chromatin immunoprecipitation, we demonstrate that Zac1 binds the TGF-β1 and COL6A2 promoters, forming a direct pathway between imprinted genes and well-characterized pathophysiological mechanisms of NAFLD. Finally, we show that hepatocyte-specific over-expression of Zac1 is sufficient to drive fibrosis in vivo. Conclusions Our findings identify a novel pathway linking maternal MetS exposure during postnatal development to the programming of juvenile NAFLD, and provide support for the hypothesis that imprinted genes play a central role in metabolic disease programming.
2022-02-14 | GSE183809 | GEO
Project description:Background and Aims Within the next decade, non-alcoholic fatty liver disease (NAFLD) is predicted to become the most prevalent cause of childhood liver failure in developed countries. Predisposition to juvenile NAFLD can be programmed during early life in response to maternal metabolic syndrome (MetS), but the underlying mechanisms are poorly understood. We hypothesized that imprinted genes, defined by expression from a single parental allele, play a key role in maternal MetS-induced NAFLD, due to their susceptibility to environmental stressors and their functions in liver homeostasis. We aimed to test this hypothesis and determine the critical periods of susceptibility to maternal MetS. Approach and Results We established a mouse model to compare the effects of MetS during prenatal and postnatal development on NAFLD. Postnatal but not prenatal MetS exposure is associated with histological, biochemical and molecular signatures of hepatic steatosis and fibrosis in juvenile mice. Using RNA-seq, we show that the Imprinted Gene Network (IGN), including its regulator Zac1, is up-regulated and over-represented among differentially expressed genes, consistent with a role in maternal MetS-induced NAFLD. In support of this, activation of the IGN in cultured hepatoma cells by over-expressing Zac1 is sufficient to induce signatures of profibrogenic transformation. Using chromatin immunoprecipitation, we demonstrate that Zac1 binds the TGF-β1 and COL6A2 promoters, forming a direct pathway between imprinted genes and well-characterized pathophysiological mechanisms of NAFLD. Finally, we show that hepatocyte-specific over-expression of Zac1 is sufficient to drive fibrosis in vivo. Conclusions Our findings identify a novel pathway linking maternal MetS exposure during postnatal development to the programming of juvenile NAFLD, and provide support for the hypothesis that imprinted genes play a central role in metabolic disease programming.
2022-02-14 | GSE193670 | GEO
Project description:Background and Aims: Cadmium (Cd) exposure in adulthood is associated with non-alcoholic fatty liver disease (NAFLD), characterized by steatosis, inflammation, and fibrosis. NAFLD is the leading type of chronic liver disease, resulting in $103 billion per year in medical costs and affecting 30 % of the adult US population. Diagnosis of NAFLD is occurring at increasingly younger ages, with up to 20 % of adolescents and young adults currently affected, suggesting that susceptibility to NAFLD may be programmed by the environment during early life. However, the role of developmental Cd exposure in programming NAFLD and the underlying mechanisms remain unclear. We have proposed that imprinted genes are strong candidates for connecting the early life environment and later disease. Approach and Results: We established a hybrid mouse model of developmental Cd exposure in which dams were exposed to 0 or 50 ppm CdCl2 five weeks prior to mating until their offspring reached postnatal day (PND) 10. CdCl2 exposure is associated with histological, biochemical, and molecular signatures of hepatic steatosis and fibrosis in juvenile mice. Using RNA-seq, we show that the Imprinted Gene Network (IGN), including its regulator Zac1, is up-regulated and over-represented among differentially expressed genes, consistent with a role in developmental Cd-induced NAFLD. In support of this, we show that hepatocyte-specific over-expression of Zac1 is sufficient to drive lipid accumulation in vitro. Conclusions: Our findings demonstrate that developmental CdCl2 exposure is sufficient to program NAFLD in later life, and with our previous work, establish Zac1 and the IGN as key regulators of prosteatotic and profibrotic pathways, two of the major pathological hallmarks of NAFLD
2022-10-21 | GSE201906 | GEO
Project description:PLAGL1/ZAC1 undergoes parental genomic imprinting, is paternally expressed, and is a member of the imprinted gene network (IGN). It encodes a zinc finger transcription factor with anti-proliferative activity and is a candidate tumor suppressor gene on 6q24 whose expression is frequently lost in various neoplasms. Conversely, gain of PLAGL1 function is responsible for transient neonatal diabetes mellitus, a rare genetic disease that results from defective pancreas development. In the present work, we showed that Plagl1 up-regulation was not associated with DNA damage-induced cell cycle arrest. It was rather associated with physiological cell cycle exit that occurred with contact inhibition, growth factor withdrawal, or cell differentiation. To gain insights into Plagl1 mechanism of action, we identified Plagl1 target genes by combining chromatin immunoprecipitation and genome-wide transcriptomics in transfected cell lines. Plagl1-elicited gene regulation correlated with multiple binding to the proximal promoter region through a GC-rich motif. Plagl1 target genes included numerous genes involved in signaling, cell adhesion, and extracellular matrix composition, including collagens. Plagl1 targets also included 22% of the 409 genes that make up the IGN. Altogether, this work identified Plagl1 as a transcription factor that coordinated the regulation of a subset of IGN genes and controlled extracellular matrix composition.
| S-EPMC5737700 | biostudies-literature
Project description:The hypocretin/orexin neuropeptide system coordinates the regulation of various physiological processes. Our previous study reported that a reduction in the expression of pleomorphic adenoma gene‑like 1 (Plagl1), which encodes a C2H2 zinc‑finger transcription factor, occurs in hypocretin neuron‑ablated transgenic mice, suggesting that PLAGL1 is co‑expressed in hypocretin neurons and regulates hypocretin transcription. The present study examined whether canonical prepro‑hypocretin transcription is functionally modulated by PLAGL1. Double immunostaining indicated that the majority of hypocretin neurons were positive for PLAGL1 immunoreactivity in the nucleus. Notably, PLAGL1 immunoreactivity in hypocretin neurons was altered in response to several conditions affecting hypocretin function. An uneven localization of PLAGL1 was detected in the nuclei of hypocretin neurons following sleep deprivation. Chromatin immunoprecipitation revealed that endogenous PLAGL1 may bind to a putative PLAGL1‑binding site in the proximal region of the hypocretin gene, in the murine hypothalamus. In addition, electroporation of the PLAGL1 expression vector into the fetal hypothalamus promoted hypothalamic hypocretin transcription. These results suggested that PLAGL1 may regulate hypothalamic hypocretin transcription.
| S-EPMC6445593 | biostudies-literature
Project description:Genome-wide characterization of Zac1 target genes reveals its role as a broad regulator of the imprinted gene network including extracellular matrix genes
| PRJNA306039 | ENA
Project description:Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin mono-allelic expression of a small subset of mammalian genes. Imprinted genes have been categorized into two groups: multi lineage (ML) imprinted genes that can show imprinted expression in both embryonic and extra-embryonic lineages, and genes that show extra-embryonic lineage (EXEL) specific imprinted expression restricted to tissues like the placenta and visceral yolk sac (VYS) endoderm. Many genes showing EXEL imprinted expression are silenced by lncRNAs that act over long distances. Thus the analysis of this form of gene silencing is likely to be pivotal for understanding new mechanisms of long range gene silencing by lncRNAs. It has been reported that ES cells differentiated into cystic embryoid bodies (cystic EBs) contain VYS endoderm and here we investigate if cystic EBs could serve as an in vitro model for the analysis of EXEL imprinted expression. Unexpectedly we found that cystic EBs lack EXEL imprinted expression, while retaining normal imprinted expression of ML genes. This shows that cystic EBs do not model VYS imprinted expression and also argues against previous claims that cystic EBs contain VYS endoderm. We further characterized cystic EBs by performing RNA-seq and whole genome bisulphite sequencing. By comparison to various embryonic tissues we found that cystic EBs more resemble embryonic liver, which contains definitive endoderm, than the extra-embryonic endoderm of the VYS. Examination of gene and retrotranssposone expression and DNA methylation in extraembryonic, embryonic tissues and ES cell diferentiated as cystic EBs
2015-07-22 | E-GEOD-56276 | biostudies-arrayexpress