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Bromate-induced Changes in p21 DNA Methylation and Histone Acetylation in Renal Cells.

ABSTRACT: Bromate (BrO3-) is a water disinfection byproduct (DBP) previously shown to induce nephrotoxicity in vitro and in vivo. We recently showed that inhibitors of DNA methyltransferase 5-aza-2'-deoxycytidine (5-Aza) and histone deacetylase trichostatin A (TSA) increased BrO3- nephrotoxicity whereas altering the expression of the cyclin-dependent kinase inhibitor p21. Human embryonic kidney cells (HEK293) and normal rat kidney (NRK) cells were sub-chronically exposed to BrO3- or epigenetic inhibitors for 18 days, followed by 9 days of withdrawal. DNA methylation was studied using a modification of bisulfite amplicon sequencing called targeted gene bisulfite sequencing. Basal promoter methylation in the human p21 promoter region was substantially lower than that of the rat DNA. Furthermore, 5-Aza decreased DNA methylation in HEK293 cells at the sis-inducible element at 3 distinct CpG sites located at 691, 855, and 895 bp upstream of transcription start site (TSS). 5-Aza also decreased methylation at the rat p21 promoter about 250 bp upstream of the p21 TSS. In contrast, sub-chronic BrO3- exposure failed to alter methylation in human or rat renal cells. BrO3- exposure altered histone acetylation in NRK cells at the p21 TSS, but not in HEK293 cells. Interestingly, changes in DNA methylation induced by 5-Aza persisted after its removal; however, TSA- and BrO3--induced histone hyperacetylation returned to basal levels after 3 days of withdrawal. These data demonstrate novel sites within the p21 gene that are epigenetically regulated and further show that significant differences exist in the epigenetic landscape between rat and human p21, especially with regards to toxicant-induced changes in histone acetylation.

SUBMITTER: Kolli RT

PROVIDER: S-EPMC6432867 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Bromate-induced Changes in p21 DNA Methylation and Histone Acetylation in Renal Cells.

Kolli Ramya T RT Glenn Travis C TC Brown Bradley T BT Kaur Sukhneeraj P SP Barnett Lillie M LM Lash Lawrence H LH Cummings Brian S BS

Toxicological sciences : an official journal of the Society of Toxicology 20190401 2

Bromate (BrO3-) is a water disinfection byproduct (DBP) previously shown to induce nephrotoxicity in vitro and in vivo. We recently showed that inhibitors of DNA methyltransferase 5-aza-2'-deoxycytidine (5-Aza) and histone deacetylase trichostatin A (TSA) increased BrO3- nephrotoxicity whereas altering the expression of the cyclin-dependent kinase inhibitor p21. Human embryonic kidney cells (HEK293) and normal rat kidney (NRK) cells were sub-chronically exposed to BrO3- or epigenetic inhibitors ...[more]

PMID: 30649504

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Project description:BACKGROUND:Glial cell line-derived neurotrophic factor (GDNF) is highly expressed in glioblastoma (GBM) and blocking its expression can inhibit the initiation and development of GBM. GDNF is a dual promoter gene, and the promoter II with two enhancers and two silencers plays a major role in transcription initiation. We had previously reported that histone hyperacetylation and DNA hypermethylation in GDNF promoter II region result in high transcription of GDNF in GBM cells, but the mechanism remains unclear. In this study, we investigated whether these modifications synergistically regulate high GDNF transcription in GBM. RESULTS:Cyclic AMP response element binding protein (CREB) expression and phosphorylation at S133 were significantly increased in human GBM tissues and GBM cell lines (U251 and U343). In U251 GBM cells, high expressed CREB significantly enhanced GDNF transcription and promoter II activity. CREB regulated GDNF transcription via the cyclic AMP response elements (CREs) in enhancer II and silencer II of GDNF promoter II. However, the two CREs played opposite regulatory roles. Interestingly, hypermethylation of CRE in silencer II occurred in GBM tissues and cells which led to decreased and increased phosphorylated CREB (pCREB) binding to silencer II and enhancer II, respectively. Moreover, pCREB recruited CREB binding protein (CBP) with histone acetylase activity to the CRE of GDNF enhancer II, thereby increasing histone H3 acetylation and RNA polymerase II recruitment there and at the transcription start site (TSS), and promoted GDNF high transcription in U251 cells. The results indicated that high GDNF transcription was attributable to DNA hypermethylation in CRE of GDNF silencer II increasing pCREB binding to CRE in enhancer II, which enhanced CBP recruitment, histone H3 acetylation, and RNA polymerase II recruitment there and at the TSS. CONCLUSIONS:Our results demonstrate that pCREB-induced crosstalk between DNA methylation and histone acetylation at the GDNF promoter II enhanced GDNF high transcription, providing a new perspective for GBM treatment.

Dataset Information

Bromate-induced Changes in p21 DNA Methylation and Histone Acetylation in Renal Cells.

Publications

Bromate-induced Changes in p21 DNA Methylation and Histone Acetylation in Renal Cells.

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