Exacerbated Salmonellosis in poly(ADP-ribose) polymerase 14 deficient mice
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ABSTRACT:
PROVIDER: PRJNA1198343 | ENA |
REPOSITORIES: ENA
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Project description:Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis
| PRJNA1062760 | ENA
Project description:Poly(ADP-ribose) polymerase 1 (PARP1) critically facilitates DNA damage response (DDR) that suppresses genomic instability. However, the physiological function of PARP1 in regulating genomic integrity is unclear. We investigated the Ewing’s sarcoma breakpoint region 1 (EWS) and found that it regulated the physiological function of PARP1. EWS was indispensable to dissociation of PARP1 from damaged DNA, promoting DDR and regulating DDR protein expression. Abnormal PARP1 accumulation due to EWS expression silencing, induced hyper-PARylation, which exhausted cellular NAD+ levels and caused cell death in in vitro and in vivo. Positively charged EWS arginine-glycine-glycine (Arg-Gly-Gly, RGG) domains directly interact with poly ADP-ribose (PAR) chains produced by PARP1 and are essential to dissociate PARP1 from damaged DNA. Consistently, Ewing’s sarcoma cells with defective EWS function accumulated PARP1 on chromatin and tissues from Ewing’s sarcoma patients, exhibiting high PARylation levels. Taken together, loss of EWS causes defects in PARP1 dissociation and results in genomic instability.
2020-11-03 | PXD016145 | Pride
Project description:Salmonella enterica serovar Typhimurium infection triggers a robust immune response in the host, but the molecular mechanisms regulating this response are not fully understood. Parp14 has been shown to enhance type I interferon responses and influence bacterial resistance, particularly in macrophages. To explore the role of Parp14 in immune regulation, we investigated Salmonella infection in Parp14 knockout mice over 5 days. On day 1 post-infection (p.i.), Parp14-deficient mice displayed elevated bacterial loads in the liver, but no differences in other tissues. By day 5, bacterial counts in the proximal colon were slightly lower in Parp14 knockout mice compared to wild-type controls, suggesting Parp14 regulates immune responses across multiple cell types, including epithelial cells. Histopathological analyses revealed increased immune cell infiltration, goblet cell loss, and tissue erosion in the proximal colon of Parp14-deficient mice on day 5 p.i. RNA-seq data from proximal colon tissue identified impaired expression of immune response genes, including Ccl2, Il1b, and Il6, which are critical for early-stage infection defense. Further analysis revealed downregulation of genes involved in cellular adhesion and cytoskeleton maintenance. These findings indicate that Parp14 is essential for an effective early innate immune response and for maintaining epithelial integrity during Salmonella infection, highlighting its potential as a therapeutic target for bacterial infections.
2024-12-26 | GSE284287 | GEO
Project description:Poly(ADP-ribose) polymerase 3 (PARP3) is a member of the PARP family of enzymes. It is structurally related to the well characterized type member PARP1 that orchestrates DNA strand break repair and cell death by the synthesis of poly(ADP-ribose). In contrast, the functions of PARP3 are undefined. We have used several in vitro and in vivo approaches to examine the possible functions of PARP3 as a transcriptional regulator, a function suggested from its previously reported association with several Polycomb group (PcG) proteins. A ChIP-chip analysis of PARP3 gene occupancy in the human neuroblastoma cell line SK-N-SH reveals that PARP3 is preferentially associated with developmental genes and is significantly enriched around the transcriptional start site of several genes encoding neuronal and sensory placodes specifiers, such as SOX9, DLX3 and DLX4. Using zebrafish as a vertebrate animal model, we demonstrate that Parp3 plays a key role in ectodermal and neural crest specification. Morpholino oligonucleotide-directed inhibition of parp3 expression in zebrafish impairs the expression of the neural crest cell specifier sox9a and of dlx3b/dlx4b, the formation of cranial sensory placodes, inner ears and pectoral fins. It delays pigmentation and severely impedes the development of the median fin fold and tail bud. Our findings demonstrate that Parp3 is crucial in the early stages of zebrafish development, possibly by exerting its transcriptional regulatory functions as early as during the specification of the neural plate border. ChIP were conducted as described (Rodrigue et al. 2006). PARP3 was immunoprecipitated from 3 x 10^7 SK-N-SH cells with a commercial anti-PARP3 (Enzo Life Sciences ALX-210-541). In control ChIP, PARP3 antibodies were replaced by rabbit IgG. Two independent PARP3 and control ChIP-chip experiments were achieved. The DNA was amplified using LM-PCR and labelled with Cy5 (PARP3) and Cy3 (IgG) before hybridization on Agilent Human promoter arrays (two 244k chip per ChIP for a total of 4 chips). Detailed protocols can be found at http://www.ircm.qc.ca/microsites/francoisrobert/en. Regions significantly enriched for PARP3 relative to IgG were identified as described (Lee et al. 2006).
2011-08-17 | E-GEOD-23709 | biostudies-arrayexpress
Project description:To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. Mnase sensitivity of sperm DNA, indicating nucleosomal, not protamine, packaging was altered in mice by manipulating poly(ADP-ribose) metabolism in adult males using a specific PARP inhibitor for 6 weeks. Abnormal sperm nucleosomal organization of males analyzed by these tiling arrays was compared with differential gene expression in 2 cell embryos fathered by these males analyzed by separate gene expression arrays and RNA sequencing.
2014-08-30 | E-GEOD-56282 | biostudies-arrayexpress
Project description:Poly(ADP-ribose) polymerase 3 (PARP3) is a member of the PARP family of enzymes. It is structurally related to the well characterized type member PARP1 that orchestrates DNA strand break repair and cell death by the synthesis of poly(ADP-ribose). In contrast, the functions of PARP3 are undefined. We have used several in vitro and in vivo approaches to examine the possible functions of PARP3 as a transcriptional regulator, a function suggested from its previously reported association with several Polycomb group (PcG) proteins. A ChIP-chip analysis of PARP3 gene occupancy in the human neuroblastoma cell line SK-N-SH reveals that PARP3 is preferentially associated with developmental genes and is significantly enriched around the transcriptional start site of several genes encoding neuronal and sensory placodes specifiers, such as SOX9, DLX3 and DLX4. Using zebrafish as a vertebrate animal model, we demonstrate that Parp3 plays a key role in ectodermal and neural crest specification. Morpholino oligonucleotide-directed inhibition of parp3 expression in zebrafish impairs the expression of the neural crest cell specifier sox9a and of dlx3b/dlx4b, the formation of cranial sensory placodes, inner ears and pectoral fins. It delays pigmentation and severely impedes the development of the median fin fold and tail bud. Our findings demonstrate that Parp3 is crucial in the early stages of zebrafish development, possibly by exerting its transcriptional regulatory functions as early as during the specification of the neural plate border.
2011-08-18 | GSE23709 | GEO
Project description:Post-translational modifications, such as poly(ADP-ribosyl)ation (PARylation), regulate chromatin-modifying enzymes, ultimately affecting gene expression. This study explores the role of poly(ADP-ribose) polymerase (PARP) on global gene expression in a lymphoblastoid B cell line. We found that inhibition of PARP catalytic activity with olaparib resulted in global gene deregulation, affecting approximately 11% of genes expressed. Gene ontology analysis revealed that PARP could exert these effects through transcription factors and chromatin-remodeling enzymes, including the Polycomb Repressive Complex 2 (PRC2) member EZH2. EZH2 mediates the trimethylation of histone H3 at lysine 27 (H3K27me3), a modification associated with chromatin compaction and gene silencing. Both pharmacological inhibition of PARP and knockdown of PARP1 induced the expression of EZH2 that resulted in increased global H3K27me3. Chromatin immunoprecipitation confirmed that PARP1 inhibition led to H3K27me3 deposition at EZH2-target genes, which resulted in gene silencing. Moreover, increased EZH2 expression is attributed to occupancy loss of the transcription repressor E2F4 at the EZH2 promoter following PARP inhibition. Together, these data show that PARP plays an important role in global gene regulation and identifies for the first time a direct role of PARP1 in regulating the expression and function of EZH2.
2015-11-13 | GSE74974 | GEO
Project description:Inflammatory bowel disease (IBD) is a debilitating and relapsing chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly (ADP-ribose) polymerase 14 (Parp14), an important regulator of immune cells functions, using a biobank IBD patient cohort as well as the oral dextran sulfate sodium (DSS) exposure mouse IBD colitis, and, in parallel, the oral Salmonella exposure mouse colitis models. Parp14 was expressed in the human colon, by cells in the lamina propria, but, in particular, by the epithelial cells with a typical granular staining pattern in the cytosol. The same Parp14 staining pattern was evidenced in both mouse models. Body-wide genetic deficiency of Parp14 in C57BL/6N background sensitized mice to DSS colitis, i.e., the Parp14-deficient mice displayed increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss and immune cell infiltration. The absence of Parp14 did not cause mouse colon bacterial dysbiosis based on PacBio long read sequencing. Also, the colon leukocyte populations of Parp14-deficient mice appeared nominal based on flow cytometry. In contrast, we witnessed an altered transcriptional signature in Parp14-deficient mice with bulk tissue RNA-Seq. Gene Ontology (GO)-based classification of differentially expressed genes demonstrated that the colon transcriptional signature of Parp14-deficient mice was dominated by abnormalities in inflammation and infection response both prior and after the DSS exposure. The data indicate that Parp14 has an important role in the maintenance of epithelial barrier integrity in colitis, and that Parp14 may have functions also outside the immune cell compartment. The prognostic and predictive biomarker potential of Parp14 as well as its mutational landscape in IBD merits further investigation.
2024-01-13 | GSE252812 | GEO
Project description:The etiology of Parkinson’s disease (PD) remains elusive, and the limited availability of suitable animal models hampers research on pathogenesis and drug development. We report the development of a cynomolgus monkey model of PD that combines AAV-mediated overexpression of α-synuclein into the substantia nigra with injection of Poly(ADP-ribose) (PAR) into the striatum. Our results show that pathological processes were accelerated, including dopaminergic neuron degeneration, Lewy Bodies aggregation, and hallmarks of inflammation in microglia and astrocytes. Behavioral phenotypes, dopamine transporter imaging and transcriptomic profiling further demonstrate consistencies between the model and PD patients. This model can help to determine mechanisms underlying PD impacted by α-synuclein and PAR and aid in accelerated development of therapeutic strategies for PD.
2024-09-20 | GSE276753 | GEO
Project description:To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. Mnase sensitivity of sperm DNA, indicating nucleosomal, not protamine, packaging was altered in mice by manipulating poly(ADP-ribose) metabolism in adult males using Parg gene disruption (Parg(110)-/-). Abnormal sperm nucleosomal organization of males analyzed by these tiling arrays was compared with differential gene expression in individual 2 cell embryos fathered by these males analyzed in separate expression microarrays.
2014-08-30 | E-GEOD-56281 | biostudies-arrayexpress