Deep analysis of FANTOM CAGE data reveals hierarchical patterns of TSS co-deployment hubs and their disruption in cancers

Selective deployment of multiple transcription start sites is a major regulatory feature of human transcriptomes. FANTOM CAGE data exhibit a near-universal TSS deployment parsimony which is disrupted in cancers. We have recently shown that TSS deployment is sensitive to gene function, futile upstream transcription, and cellular biosynthetic states. Patterns in FANTOM CAGE data can reveal mechanisms underlying TSS co-deployments. We propose and test the possibility that some TSSs act like epromoters and act as co-varying hubs of transcriptional activities for multiple other promoters. Using deep analysis of CAGE data implemented through neural networks we show that non-cancers implement transcription co-deployments through cores of epromoter-like TSSs which are generally proximal to their start codons. These TSSs show enhancer-like TFBSs profiles. A comparison with cancer CAGE data shows that the concentrated epromoter core is disrupted in cancers with multiple distal TSSs replacing the proximal TSS cores. We provide evidence that the core TSSs are rich in YY1 and CTCF binding sites and associated with genes coding for transcription factors. Our findings show that covariance of TSS deployment is sensitive to transcriptional resource cost and a parsimonic design of TSS co-deployments depends on proximal TSSs in non-cancers, a mechanism grossly disrupted in cancers. Highlights Heterogeneous FANTOM CAGE data contains universal patterns of TSSs co-deployments. TSS co-deployments exhibit a parsimonious “core-covariant” scheme which is disrupted in cancers. Core TSSs are enriched in transcription factor binding sites and gene functions which justify biological features of the samples. The DL pipeline we present identifies the core-covariant TSS sets in an unbiased manner.