Long-Range Chromatin Interaction Regulates hTERT Expression Through Epigenetic Modifications

Abstract

hTERT gene is heavily under control of epigenetic mechanisms which regulates its transcription. This transcriptional regulation is in most cases the limiting component for telomerase activity. However, telomerase is re-activated in 85% of cancers and this re-activation of hTERT has a complex mechanism in cancers. Recently, highly frequent substitution mutations have been observed in the proximal promoter of the hTERT gene. These correlated with increased hTERT expression and telomerase activity in cancers. These mutations create de novo ETS binding motifs, which alter the chromatin organization by mediating formation of long-range chromatin interaction between hTERT promoter and distal regions of chromatin with multiple ETS binding motifs. This specific chromatin interaction alters the epigenetic features of the hTERT promoter and explains how hTERT expression is increased in cancer cells with hTERT promoter mutations.