DNMT and HDAC inhibitors globally induce cryptic TSSs encoded in long terminal repeats

By mapping global transcription start site (TSS) and chromatin dynamics, we observed the activation of thousands of cryptic, currently non-annotated TSSs (TINATS) following DNMTi and/or HDACi treatment. The resulting transcripts encode truncated or chimeric open reading frames that can be translated into products with predicted abnormal functions or immunogenic potential. TINAT activation after DNMTi coincided with DNA hypomethylation and gain in H3K4me3, H3K9ac, and H3K27ac histone marks. In contrast, HDACi induced only canonical TSSs in association with histone acetylation, but TINATs via a yet unknown mechanism. Nevertheless, both inhibitors convergently induced unidirectional transcription from identical sites since TINATs are encoded in solitary long-terminal repeats of the endogenous retrovirus-9 family, epigenetically repressed in virtually all normal cells. Overall design: CAGE-, ChIP-, and WGB-sequencing of NCI-H1299 EGFP-NEO reporter cells after treatment with DMSO, DAC, SB939, or DAC+SB

10

Brocks D, Schmidt CR, Daskalakis M, Jang HS, Shah NM, Li D, Li J, Zhang B, Hou Y, Laudato S, Lipka DB, Schott J, Bierhoff H, Assenov Y, Helf M, Ressnerova A, Islam MS, Lindroth AM, Haas S, Essers M, Imbusch CD, Brors B, Oehme I, Witt O, Lübbert M, Mallm JP, Rippe K, Will R, Weichenhan D, Stoecklin G, Gerhäuser C, Oakes CC, Wang T, Plass C