Redistribution of chromatin binding of tumor suppressors drive transcriptional reprogramming in HRas-induced transformation

Gene transcription is substantially regulated by distant regulatory elements via combinatorial binding of transcription factors. It is more and more recognized that alterations in chromatin state and transcription factor binding in these distant regulatory elements may have key roles in cancer development. Here we focused on the first stages of oncogene induced carcinogenic transformation, and characterized the regulatory network underlying transcriptional reprogramming associated with this process. Using Hi-C data, we couple between differentially expressed genes and their differentially active regulatory elements and reveal two candidate transcription factors, p53 and CTCF, as major determinants of transcriptional reprogramming at early stages of HRas-induced transformation. Strikingly, the malignant transcriptional reprograming is promoted by redistribution of chromatin binding of these factors without major variation in their expression level. Our results demonstrate that alterations in the regulatory landscape have a major role in driving oncogene-induced transcriptional reprogramming.