DNA methylation of METTL7A gene body regulates its transcriptional level in thyroid cancer

Abstract

DNA methylation is the best-studied epigenetic mechanism for regulating gene transcription and maintaining genome stability. Current research progress of transcriptional regulation by DNA methylation mostly focuses on promoter region where hypomethylated CpG islands are present transcriptional activity, as hypermethylated CpG islands generally result in gene repression. Recently, the DNA methylation patterns across the gene body (intragenic methylation) have increasingly attracted attention towards their role in transcriptional regulation and efficiency, due to the improvement of numerous genome-wide DNA methylation profiling studies. However, the function and mechanism of gene body methylation is still unclear. In this study, we revealed that the methylation level of METTL7A, a seldom studied gene, was downregulated in thyroid cancer compared to normal thyroid cells in vivo and in vitro. Moreover, we determined the methylation level of one CpG site at the exon of the METTL7A gene body impacted the transcriptional activity. Through generating a mutation of this CpG site (CG to CC) of METTL7A exogenous vector artificially in vitro, we observed higher RNA polymerase II recruitment and a declined enrichment of methyl-CpG binding protein-2 in gene body of METTL7A, in papillary thryoid cancer cells (BCPAP) compared to normal thryoid cells. Finally, we revealed that EZH2, a subunit of polycomb repressor complex 2, dominant in thyroid cancer, might be responsible for regulating gene body methylation of METTL7A. Our study depicted the DNA methylation patterns and the transcriptional regulatory mechanism of the gene body in thyroid cancer. Furthermore, this study provides new insight into potential future avenues, for therapies targeting cancer.