Synergistic effects of PARP inhibition and cholesterol biosynthesis modulation
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ABSTRACT:
PROVIDER: PRJNA962032 | ENA |
REPOSITORIES: ENA
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Project description:Investigate the effects of PARP inhibition in different contexts.
2023-06-01 | GSE230634 | GEO
Project description:Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme; however, recently metabolic properties had been attributed to it. Hereby, we examined the metabolic consequences of PARP-2 ablation in liver. Microarray analysis of PARP-2 knockdown HepG2 cells revealed the dysregulation of lipid and cholesterol metabolism genes. Induction of cholesterol biosynthesis genes stemmed from the enhanced expression of sterol-regulatory element binding protein (SREBP)-1. We revealed that PARP-2 is a suppressor of the SREBP-1 promoter, therefore ablation of PARP-2 induces SREBP-1 expression and consequently cholesterol synthesis. PARP-2-/- mice had higher SREBP-1 expression that was translated into enhanced hepatic and serum cholesterol levels. PARP-2 silencing was performed employing shPARP-2 (small hairpin) and scPARP-2 (scrambled) shRNA by lentiviral delivery (Sigma) using 40 MOI lentiviruses coding shRNA sequence against PARP-2.
2013-12-31 | E-GEOD-43981 | biostudies-arrayexpress
Project description:Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme; however, recently metabolic properties had been attributed to it. Hereby, we examined the metabolic consequences of PARP-2 ablation in liver. Microarray analysis of PARP-2 knockdown HepG2 cells revealed the dysregulation of lipid and cholesterol metabolism genes. Induction of cholesterol biosynthesis genes stemmed from the enhanced expression of sterol-regulatory element binding protein (SREBP)-1. We revealed that PARP-2 is a suppressor of the SREBP-1 promoter, therefore ablation of PARP-2 induces SREBP-1 expression and consequently cholesterol synthesis. PARP-2-/- mice had higher SREBP-1 expression that was translated into enhanced hepatic and serum cholesterol levels.
2013-12-31 | GSE43981 | GEO
Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked to altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity and hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
2021-06-01 | GSE169712 | GEO
Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked with altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity, hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
2021-09-10 | GSE183790 | GEO
Project description:Background: Several genetic defects of the nucleotide excision repair (NER) pathway, including deficiency of the Excision Repair Cross-Complementing rodent repair deficiency, complementation group 1 (ERCC1), result in pre-mature aging, impaired growth, microcephaly and delayed development of the cerebellum. Such a phenotype also occurs in ERCC1-knockout mice which survive for up to 4 weeks after birth. Therefore, we analyzed cerebellar and hippocamapal transcriptomes of these animals at 3 weeks of age to identify the candidate mechanisms underlying brain consequences of reduced ERCC1 activity. Results: In the cerebellum, the most prominent change was upregulation of genes that are associated with gliosis. Although Purkinje cell degeneration has been reported in some mouse strains with NER impairment, Purkinje cell transcriptome was mostly unaffected by the ERCC1 knockout. In the hippocampus, the gliosis response was minimal. Instead, there was an extensive downregulation of genes related to lipid metabolism including several enzymes of the cholesterol biosynthesis pathway as well as lipoproteins and plasma membrane proteins. Reduced expression of the cholesterol biosynthesis pathway genes was also present in the neocortex of adult mice whose ERCC1 gene was replaced by a mutant allele with a partial activity. Conclusions: Downregulation of forebrain cholesterol biosynthesis genes is a newly identified consequence of ERCC1 deficiency. Its presence in adult mice suggests that it is not a secondary consequence of brain growth impairment. Instead, reduced cholesterol biosynthesis may contribute to such an impairment as well as affect function of mature synapses. We analyzed the hippocampus and cerebellum from three Ercc1-/- and three WT littermates using the Affymetrix Mouse Genome 430_2.0. Data was analyzed using the dChip DNA-Chip analyzer software .
2011-08-15 | E-GEOD-31199 | biostudies-arrayexpress
Project description:Negative Feedback Regulation of Cholesterol Biosynthesis by MMAB
| PRJNA717749 | ENA
Project description:Cholesterol deprivation drives DHEA biosynthesis in human adrenals
| PRJNA789937 | ENA
Project description:Negative Feedback Regulation of Cholesterol Biosynthesis by MMAB
| PRJNA762016 | ENA
Project description:Expression data of medulloblastoma patient derived xenograft spheroids upon BGB 290 and romidepsin treatment alone and in combination: Romidepsin and BGB 290 shows synergistic growth inhibition in medulloblastoma patient derived xenograft spheroid models in vitro and in vivo. Chromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double-strand breaks in a one-off catastrophic event. Rearrangements associated with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double-strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n = 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses, and in vivo validation in patient-derived xenograft mouse models confirmed the efficacy of the combinatorial treatment.
2022-02-08 | GSE188894 | GEO