Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression
The ( ) gene is responsible for telomere maintenance in germline and stem cells, and is re-expressed in 90% of human cancers. Contrary to common concepts, CpG methylation in the promoter ( p), was correlated with mRNA expression. Furthermore, two hotspot mutations in p, dubbed C228T and C250T, have been revealed to assist binding of transcription factor ETS/TCF and subsequent expression. This study aimed to elucidate the combined contribution of epigenetic (promoter methylation and higher-order
... on and higher-order chromatin structure) and genetic (promoter mutations) mechanisms in regulating gene expression in healthy skin and in melanoma cell lines (n=61). We unexpectedly observed that the methylation of p was as high in a subset of healthy skin cells, mainly keratinocytes, as in cutaneous melanoma cell lines. In spite of the high promoter methylation fraction in wild-type (WT) samples, mRNA was only expressed in the melanoma cell lines with high methylation or intermediate methylation in combination with mutations. p methylation was positively correlated with chromatin accessibility and expression in 8 melanoma cell lines. Cooperation between epigenetic and genetic mechanisms were best observed in heterozygous mutant cell lines as chromosome accessibility preferentially concerned the mutant allele. Combined, these results suggest a complex model in which expression requires either a widely open chromatin state throughout the promoter in p-WT samples due to high methylation or a combination of moderate methylation fraction/chromatin accessibility in the presence of the C228T/C250T mutations.