DNMT inhibition in the Neonatal Preoptic Area
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE66203 | GEO | 2015/03/30
SECONDARY ACCESSION(S): PRJNA276102
REPOSITORIES: GEO
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Project description:PN2 male and female rat pups were treated with vehicle or zebularine. POA RNA was extracted and sequenced to deterime the effects of DNMT inhibition in POA gene expression. Males and Females were treated with either vehicle (0.1% DNMSO in saline) or Zebularine
2015-03-30 | E-GEOD-66203 | biostudies-arrayexpress
Project description:Cultures of DU-145 cells and of LNCaP cells were treated for 216 hours with 100µM zebularine (SIGMA) in three independent biological experiments. Zebularine acts as a DNA methyltransferase (DNMT) inhibitor thereby upregulating genes that are inactivated by e.g. promotor hypermethylation. The experiment aimed to search for upregulated transcripts to provide new targets for biomarker development and therapeutic use. Total RNA of untreated and treated (100µM zebularine) DU-145 cells (experiment HK_21_DU_145-HK_26_DU_145), and of untreated and treated (100µM zebularine) LNCaP cells (experiment HK_27_LNCaP-HK_32_LNCaP), were subjected to Affymetrix array analysis to detail the overall expression changes after treatment with a DNMT inhibitor. Treated cells showed no obvious signs of zebularine-induced cytotoxicity as revealed by XTT assays.
2013-10-24 | E-GEOD-51629 | biostudies-arrayexpress
Project description:Early life adversity has been linked to altered reproductive development in humans, including changes in the timing of pubertal onset and sexual activity. One common form of early life adversity is having limited access to resources. This form of early life adversity can be modeled in rodents using the limited bedding and nesting model (LBN), in which rat dams and pups are placed in a low resource environment from postnatal day (PND) 2 through 9. Our laboratory has previously shown that male rats raised in LBN conditions have elevated levels of plasma estradiol compared to control males. Female rats, on the other hand, show no effect of LBN on plasma hormone levels, pubertal timing, or estrous cycle duration in adulthood. Here, we find that LBN males also show changes in adult reproductive behaviors. LBN males acquired the suite of reproductive behaviors more quickly than their control counterparts over the course of 3 weeks of testing, showing shorter latencies to mount, intromit, and ejaculate compared to controls prior to the final week of testing. We also characterized LBN-induced gene transcription changes across sex in the medial preoptic area (mPOA) which underlies reproductive behaviors. Interestingly, there was no effect of LBN on puberty onset (as measured by preputial separation) or masculinization of the sexually dimorphic nucleus of the preoptic area (SDN/POA; as measured by calbindin immunoreactivity) in males, suggesting LBN may not exert effects on hormone-dependent measures until after puberty.
2022-02-15 | GSE174753 | GEO
Project description:Cholangiocarcinoma (CCA) is a cancer arising from the neoplastic transformation of cholangiocytes. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one) acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on CCA cells. We demonstrate that zebularine exerts an antitumor effect on CCA cells. Zebularine treatment decreased the concentrations of DNA methyltransferase (DNMT) proteins, and DNMT1 knockdown led to apoptotic cell death in the CCA cell lines TFK-1 and HuCCT1. DNA methylation analysis demonstrated that zebularine induced DNA demethylation, and the GO Biological Process terms “hemophilic cell adhesion”, “regulation of transcription, DNAdependent” and “Wnt signaling pathway” were found to be significantly enriched in association with demethylated genes. Furthermore, we observed that zebularine treatment decreased β-catenin protein levels in TFK-1 and HuCCT1 cells. These results suggest that zebularine alters DNA methylation status, and that some aspect of DNA demethylation by zebularine induces suppression of the Wnt signaling pathway, which leads to apoptotic cell death in CCA. We previously reported a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma via a DNA methylation-independent pathway. Together, our present and previous studies indicate that zebularine could function as both a DNMT inhibitor and a non-DNMT inhibitor reagent, and that, while the optimal usage of zebularine may depend on cancer type, zebularine may be useful for chemotherapy against cancer.
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Project description:The preoptic area (POA) of the hypothalamus is known to be crucial for sleep generation, but the spatial intermingling of sleep- and wake-promoting neurons makes it difficult to dissect the sleep control circuit. Here we identified a population of POA sleep-promoting neurons based on their projection target. Using a lentivirus for retrograde labeling with channelrhodopsin-2 (ChR2) followed by optogenetic manipulation and recording, we found that the POA GABAergic neurons projecting to the tuberomammillary nucleus (TMN) are both sleep active and sleep promoting. Cell type- and projection-specific rabies tracing revealed the presynaptic inputs to these neurons, including an amygdala GABAergic input that promotes wakefulness. Using single-cell RNA-seq, we identified several molecular markers for these neurons, and optogenetic activation of the POA neurons labeled by these markers confirmed their sleep-promoting effects. Together, these findings define a group of sleep-promoting neurons functionally, anatomically, and genetically.
2017-05-23 | GSE79108 | GEO
Project description:Cultures of A-498 cells were treated for 120hours with 1000µM zebularine (SIGMA) in three independent biological experiments. Zebularine acts as a DNA methyltransferase (DNMT) inhibitor thereby upregulating genes that are inactivated by e.g. promotor hypermethylation. The experiment aimed to search for upregulated transcripts to provide new targets for biomarker development and therapeutic use. 308 candidates were upregulated more than 1.5-fold. Members of the metallothionein group (MT1G, MT1H, and MT2A) were validated in 49 clinical samples of renal cell carcinomas. Total RNA of treated (1000µM zebularine) and untreated A-498 cells (experiment A05-A07) was subjected to Affymetrix array analysis to detail the overall expression changes after treatment with a DNMT inhibitor. Treated cells showed no obvious signs of zebularine-induced cytotoxicity as revealed by XTT assays. Cell were split twice during the 120hour treatment period.
2013-10-24 | E-GEOD-51627 | biostudies-arrayexpress
Project description:Cultures of DU-145 cells and of LNCaP cells were treated for 216 hours with 100µM zebularine (SIGMA) in three independent biological experiments. Zebularine acts as a DNA methyltransferase (DNMT) inhibitor thereby upregulating genes that are inactivated by e.g. promotor hypermethylation. The experiment aimed to search for upregulated transcripts to provide new targets for biomarker development and therapeutic use.
2013-10-24 | GSE51629 | GEO
Project description:Dexamethasone (1ug/g, Dex) or vehicle (saline) injected into postnatal days 0-7 (P0 to P7) of C57BL6J mouse pups every day. Whole organ were harvested at P7.
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Project description:Decitabine and Azacytidine are considered as epigenetic drugs that induce DNA-methyltransferase (DNMT)-DNA crosslinks, resulting in DNA-hypomethylation and -damage. Although they are already applied against myeloid cancers, important aspects of their mode of action remain unknown, highly limiting their clinical potential. Using a combinatorial approach, we reveal that the efficacy profile of both compounds primarily depends on the level of induced DNA-damage. Under low DNMT-activity, only Decitabine has a substantial impact. Conversely, when DNMT-activity is high, toxicity and cellular response to both compounds are dramatically increased, but do not primarily depend on DNA-hypomethylation or RNA-associated processes. By investigating proteome dynamics on chromatin, we show that Decitabine induces a strictly DNMT-dependent multifaceted DNA-damage response based on chromatin-recruitment, but not expression level changes of repair-associated proteins. The choice of DNA-repair pathway herby depends on the severity of Decitabine-induced DNA-lesions. While under moderate DNMT-activity, mismatch (MMR), base-excision (BER) and Fanconi anemia-dependent DNA-repair combined with homologous recombination are activated in response to Decitabine, high DNMT-activity and therefore immense replication stress, induce activation of MMR and BER followed by non-homologous end-joining.
2024-06-19 | PXD045353 | Pride
Project description:Cultures of A-498 cells were treated for 120hours with 1000µM zebularine (SIGMA) in three independent biological experiments. Zebularine acts as a DNA methyltransferase (DNMT) inhibitor thereby upregulating genes that are inactivated by e.g. promotor hypermethylation. The experiment aimed to search for upregulated transcripts to provide new targets for biomarker development and therapeutic use. 308 candidates were upregulated more than 1.5-fold. Members of the metallothionein group (MT1G, MT1H, and MT2A) were validated in 49 clinical samples of renal cell carcinomas.
2013-10-24 | GSE51627 | GEO