Dynamic interaction of MYC enhancer RNA with YEATS2 protein regulates MYC gene transcription in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most prevalent and aggressive forms of pancreatic cancer with low survival rates and limited treatment options. Aberrant expression of the MYC oncogene promotes PDAC progression. Recent reports have established a role for enhancer RNAs (eRNAs), originating from active enhancers, in controlling gene transcription. Here we show that a novel MYC eRNA regulates MYC gene expression during chronic inflammatory conditions in pancreatic cancer cells. A higher amount of MYC eRNA is observed in chronic pancreatitis and in pancreatic cancer patients. We show that MYC eRNA interacts with YEATS2, a histone reader protein of the ATAC-HAT complex, and augments the association of YEATS2-containing ATAC complexes with MYC promoter/enhancer regions and thus increases MYC gene expression. TNF-α induced Tyrosine dephosphorylation of the YEATS domain increases MYC eRNA binding to the YEATS2 protein in pancreatic cancer cells. Our study adds another regulatory layer of MYC gene expression by enhancer-driven transcription.