Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression

Catarina Salgado, Celine Roelse, Rogier Nell, Nelleke Gruis, Remco van Doorn, Pieter van der Velden
2019 biorxiv/medrxiv  
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
more » ... 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.
doi:10.1101/859892 fatcat:ygqwfnpsarbmppdgqxes56zo3u