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Gene expression profile for male SD rats treated with high fat diet (HFD) and DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5-AzaD) by RNA-Seq

ABSTRACT: To investigate the effects of HFD on affecting the gene expressions, as well as the methylation inhibitor 5-AzaD reversing such effects in the frontal cortex of male SD rats by RNA-Seq.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE64947 | GEO | 2017/12/31

SECONDARY ACCESSION(S): PRJNA272550

REPOSITORIES: GEO

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DNA methylation profile for male SD rats treated with high fat diet (HFD) and DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5-AzaD) by RRBS

Project description:To investigate the effects of HFD on affecting the DNA methylation, as well as the methylation inhibitor 5-AzaD reversing such effects in the frontal cortex of male SD rats by sequencing the methylome (RRBS).

2017-12-31 | GSE64948 | GEO

Male SD rats treated with high fat diet (HFD) and DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-AzaD)

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-12-31 | GSE64949 | GEO

Male SD rats treated with high fat diet (HFD) and DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-AzaD)

Project description:Male SD rats treated with high fat diet (HFD) and DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-AzaD)

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AID downregulation is a novel function of the DNMT inhibitor 5-aza-deoxycytidine.

Project description:Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutation (SHM) and class switch recombination (CSR) in immunoglobulin genes. However, AID can also cause mutations in host genes and contribute to cancer progression and drug resistance. In this study, molecular docking showed the interaction of free 5-aza-CdR and Zebularine (Zeb) with AID. However, only 5-aza-CdR-incorporated ssDNA bound to the active site of AID and inhibited AID expression through proteasomal degradation. 5-aza-CdR demonstrated cytotoxicity against AID-positive and -negative hematopoietic cancer cells. In contrast, Zeb exhibited a cytotoxic effect only in AID-negative cells due to its inability to inhibit AID expression. This differential effect might be due to the DNMT1 stabilization induced by AID, thus restricting the ability of Zeb to deplete DNMT1 and induce tumor suppressor genes (TSGs), such as p21, in AID-positive cells. Moreover, the in vivo anticancer effect of 5-aza-CdR but not Zeb in AID-positive hematopoietic cancer cells was demonstrated. The study not only displays the association of AID and DNMT1 and identifies a novel biological function of AID, but also provides novel information regarding the use of DNMT inhibitors to treat AID-positive hematopoietic cancers.

| S-EPMC3960202 | biostudies-literature

High DNA methyltransferase 3B expression mediates 5-aza-deoxycytidine hypersensitivity in testicular germ cell tumors.

Project description:Testicular germ cell tumors (TGCT) are the most common solid tumors of 15- to 35-year-old men. TGCT patients are frequently cured with cytotoxic cisplatin-based therapy. However, TGCT patients refractory to cisplatin-based chemotherapy have a poor prognosis, as do those having a late relapse. Pluripotent embryonal carcinomas (EC) are the malignant counterparts to embryonic stem cells and are considered the stem cells of TGCTs. Here, we show that human EC cells are highly sensitive to 5-aza-deoxycytidine (5-aza-CdR) compared with somatic solid tumor cells. Decreased proliferation and survival with low nanomolar concentrations of 5-aza-CdR is associated with ATM activation, H2AX phosphorylation, increased expression of p21, and the induction of genes known to be methylated in TGCTs (MGMT, RASSF1A, and HOXA9). Notably, 5-aza-CdR hypersensitivity is associated with markedly abundant expression of the pluripotency-associated DNA methyltransferase 3B (DNMT3B) compared with somatic tumor cells. Knockdown of DNMT3B in EC cells results in substantial resistance to 5-aza-CdR, strongly indicating that 5-aza-CdR sensitivity is mechanistically linked to high levels of DNMT3B. Intriguingly, cisplatin-resistant EC cells retain an exquisite sensitivity to low-dose 5-aza-CdR treatment, and pretreatment of 5-aza-CdR resensitizes these cells to cisplatin-mediated toxicity. This resensitization is also partially dependent on high DNMT3B levels. These novel findings indicate that high expression of DNMT3B, a likely byproduct of their pluripotency and germ cell origin, sensitizes TGCT-derived EC cells to low-dose 5-aza-CdR treatment.

| S-EPMC2795063 | biostudies-literature

Antineoplastic activity of the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine in anaplastic large cell lymphoma.

Project description:DNA methylation is an epigenetic mechanism establishing long-term gene silencing during development and cell commitment, which is maintained in subsequent cell generations. Aberrant DNA methylation is found at gene promoters in most cancers and can lead to silencing of tumor suppressor genes. The DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) is able to reactivate genes silenced by DNA methylation and has been shown to be a very potent epigenetic drug in several hematological malignancies. In this report, we demonstrate that 5-aza-CdR exhibits high antineoplastic activity against anaplastic large cell lymphoma (ALCL), a rare CD30 positive non-Hodgkin lymphoma of T-cell origin. Low dose treatment of ALCL cell lines and xenografted tumors causes apoptosis and cell cycle arrest in vitro and in vivo. This is also reflected in genome-wide expression analyses, where genes related to apoptosis and cell death are amongst the most affected targets of 5-aza-CdR. Furthermore, we observed demethylation and re-expression of p16(INK4A) after drug administration and senescence associated ?-galactosidase activity. Thus, our data provide evidence that 5-aza-CdR is highly efficient against ALCL and warrants further clinical evaluation for future therapeutic use.

| S-EPMC3480637 | biostudies-literature

A DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, exacerbates neurotoxicity and upregulates Parkinson's disease-related genes in dopaminergic neurons.

Project description:AimsTo investigate effects of DNA methyltransferase (DNMT) inhibitors on dopaminergic neurons and its underlied mechanism.MethodsThe DNMT inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) was tested in cultured dopaminergic cells. Cell viability and apoptosis were assayed with 5-aza-dC alone. Neurotoxicity of 1-methyl-4-phenylpyridinium (MPP(+) ), 6-hydroxydopamine or rotenone was also assayed with 5-aza-dC pretreatment. And mRNA levels of several key PD-related genes were examined by semiquantitative RT-PCR. Furthermore, CpG methylation of α-synuclein promoter was examined by bisulfite sequencing.Results5-aza-dC resulted in decreased cell viability and increased apoptosis in dopaminergic neuronal cells. Pretreatment with 5-aza-dC exacerbated neurotoxic damage to dopaminergic neurons induced by MPP(+) , 6-hydroxydopamine or rotenone. 5-aza-dC also induced transcriptional upregulation of the key PD-related genes tyrosine hydroxylase and α-synuclein. And demethylation of CpG in α-synuclein promoter was also induced by 5-aza-dC and MPP(+) .ConclusionsThis DNMT inhibitor might influence pathogenesis of PD. And demethylation induced by DNMT inhibitor might contribute to dopaminergic neuron death, by increasing vulnerability of dopaminergic neurons to neurotoxins and by misregulating transcription of key PD-related genes. Our data also suggested DNMT inhibitors may cause multiple effects on dopaminergic neurons.

| S-EPMC6493528 | biostudies-literature

Consequences of combining siRNA-mediated DNA methyltransferase 1 depletion with 5-aza-2'-deoxycytidine in human leukemic KG1 cells.

Project description:5-azacytidine and 5-aza-2'-deoxycytidine are clinically used to treat patients with blood neoplasia. Their antileukemic property is mediated by the trapping and the subsequent degradation of a family of proteins, the DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) leading to DNA demethylation, tumor suppressor gene re-expression and DNA damage. Here we studied the respective role of each DNMT in the human leukemia KG1 cell line using a RNA interference approach. In addition we addressed the role of DNA damage formation in DNA demethylation by 5-aza-2'-deoxycytidine. Our data show that DNMT1 is the main DNMT involved in DNA methylation maintenance in KG1 cells and in mediating DNA damage formation upon exposure to 5-aza-2'-deoxycytidine. Moreover, KG1 cells express the DNMT1 protein at a level above the one required to ensure DNA methylation maintenance, and we identified a threshold for DNMT1 depletion that needs to be exceeded to achieve DNA demethylation. Most interestingly, by combining DNMT1 siRNA and treatment with low dose of 5-aza-2'-deoxycytidine, it is possible to uncouple DNA damage formation from DNA demethylation. This work strongly suggests that a direct pharmacological inhibition of DNMT1, unlike the use of 5-aza-2'-deoxycytidine, should lead to tumor suppressor gene hypomethylation and re-expression without inducing major DNA damage in leukemia.

| S-EPMC4558150 | biostudies-literature

SD rat

Project description:SD rat Raw sequence reads

| PRJNA975055 | ENA

PBRM1 Deficiency Sensitizes Renal Cancer Cells to DNMT Inhibitor 5-Fluoro-2'-Deoxycytidine.

Project description:PBRM1 is a tumor suppressor frequently mutated in clear cell renal cell carcinoma. However, no effective targeted therapies exist for ccRCC with PBRM1 loss. To identify novel therapeutic approaches to targeting PBRM1-deficient renal cancers, we employed a synthetic lethality compound screening in isogenic PBRM1+/+ and PBRM1-/- 786-O renal tumor cells and found that a DNMT inhibitor 5-Fluoro-2'-deoxycytidine (Fdcyd) selectively inhibit PBRM1-deficient tumor growth. RCC cells lacking PBRM1 show enhanced DNA damage response, which leads to sensitivity to DNA toxic drugs. Fdcyd treatment not only induces DNA damage, but also re-activated a pro-apoptotic factor XAF1 and further promotes the genotoxic stress-induced PBRM1-deficient cell death. This study shows a novel synthetic lethality interaction between PBRM1 loss and Fdcyd treatment and indicates that DNMT inhibitor represents a novel strategy for treating ccRCC with PBRM1 loss-of-function mutations.

| S-EPMC9204009 | biostudies-literature

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