Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis

Abstract

RNA polymerase III (Pol III) transcribes medium-sized non-coding RNAs (collectively termed Pol III genes). Emerging diverse roles of Pol III genes suggest that individual Pol III genes are exquisitely regulated by transcription and epigenetic factors. Here we report global Pol III expression/methylation profiles and molecular mechanisms of Pol III regulation that have not been as extensively studied, using nc886 as a representative Pol III gene. In a human mammary epithelial cell system that recapitulates early breast tumorigenesis, the fraction of actively transcribed Pol III genes increases reaching a plateau during immortalization. Hyper-methylation of Pol III genes inhibits Pol III binding to DNA via inducing repressed chromatin and is a determinant for the Pol III repertoire. When Pol III genes are hypo-methylated, MYC amplifies their transcription, regardless of its recognition DNA motif. Thus, Pol III expression during tumorigenesis is delineated by methylation and magnified by MYC.

Protein kinase R and its cellular regulators in cancer: An active player or a surveillant?

“…It should be mentioned that Pol III activity is generally elevated in cancer (White, ) and accordingly nc886 expression increases (Park et al, ). nc886 has a strong CpG island at the promoter region and its expression is silenced in a subset of malignant cells by DNA hypermethylation at the CpG island (Park et al, ). nc886 silencing occurs frequently in a number of malignancies (Ahn et al, ; Cao et al, ; Fort et al, ; Lee, Lee, et al, ; Lee, Park, et al, ; Park et al, ; Treppendahl et al, ), presumably because nc886 is an imprinted gene (Carpenter et al, ; Paliwal et al, ; Romanelli et al, ).…”

“…nc886 has a strong CpG island at the promoter region and its expression is silenced in a subset of malignant cells by DNA hypermethylation at the CpG island (Park et al, ). nc886 silencing occurs frequently in a number of malignancies (Ahn et al, ; Cao et al, ; Fort et al, ; Lee, Lee, et al, ; Lee, Park, et al, ; Park et al, ; Treppendahl et al, ), presumably because nc886 is an imprinted gene (Carpenter et al, ; Paliwal et al, ; Romanelli et al, ). Unlike typical imprinted genes which show monoallelic methylation in 100% of individuals, nc886 is estimated to be methylated in the maternal allele in approximately 75% of individuals (Treppendahl et al, ).…”

“…For all those reasons, we surmise that nc886 is vastly superior to other PKR repressors. nc886 silencing has been observed in diverse cancers including AML (Treppendahl et al, ), small cell lung cancer (Cao et al, ), gastric cancer (Lee, Park, et al, ), esophageal cell squamous carcinoma (Lee, Lee, et al, ), breast cancer (Park et al, ), and prostate cancer (Fort et al, ). Except nc886, there is one report about P58 whose expression was shown to be lower in more malignant breast cancer cells as compared to nontransformed breast cells (Kim et al, ).…”

“…Several features of nc886, including its abundant intracellular expression and high affinity to PKR (Jeon, Lee, et al, ; Lee et al, ) as well as its expression pattern in cancer (Park et al, ), suggests that nc886 might be the most dominant determinant for PKR activity in cancer. Consistent with the general notion that PKR is a tumor suppressor, most tumor cells are assumed to have PKR activity attenuated.…”

The multi‐faceted regulation of nuclear tRNA gene transcription

“…Nc886 contains internal promoter A and B boxes, elements that both contain a CG dinucleotide. Interestingly, hypermethylation of this gene leading to its silencing has been observed in cancer cells . Similarly, whether the promoter regions of tDNAs are also subject to CG methylation, or even to CHH or CHG methylation in the case of plants where DNA methylation contexts are more widespread, will need further investigation.…”