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bioRxiv · 10.1101/2022.06.01.494372

Methylation in NDUFA13 gene promoter disrupts communication between collaborative transcription factors - potential mechanism for onset of breast cancer.

Hörberg, J.·Hallbäck, B.·Moreau, K.·Reymer, A.
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Abstract

Selective DNA binding by transcription factors (TFs) is crucial for the correct regulation of DNA transcription. In healthy cells, promoters of active genes are hypomethylated. A single CpG methylation within a TF response element may change the binding preferences of the protein thus causing the dysregulation of transcription programs. Here we investigate a molecular mechanism driving the downregulation of NDUFA13 gene, due to hypermethylation, which is associated with multiple cancers. Using bioinformatic analyses of breast cancer cell line MCF7, we identify a hypermethylated region containing the binding sites of two TFs dimers, CEBPB and E2F1-DP1, located 130 b.p. from the gene transcription start site. All-atom extended MD simulations of wild-type and methylated DNA alone and in complex with either one or both TFs dimers provide mechanistic insights into the cooperative asymmetric binding order of the two dimers; the CEBPB binding should occur first to facilitate the E2F1-DP1-DNA association. The CpG methylation within the E2F1-DP1 response element and the linker decreases the cooperativity effects and renders the E2F1-DP1 binding site less recognizable by the TF dimer. Taken together, the identified CpG methylation site may contribute to the downregulation of NDUFA13 gene and has a potential as a biomarker for breast cancer.

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Hörberg, J., Hallbäck, B., Moreau, K., Reymer, A.. 2022-06-01. Methylation in NDUFA13 gene promoter disrupts communication between collaborative transcription factors - potential mechanism for onset of breast cancer.. https://doi.org/10.1101/2022.06.01.494372

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