Elucidating altered transcriptional programs
Genetic mutations in genes involved in epigenetic-mediated mechanisms of gene regulation have been found in a broad array of solid tumors and hematologic malignancies. Each of these components of epigenetic information has been found to play a critical role in cancer.Ch IP-Seq data from AME (green) is enhanced by position site-specific matrix (PSSM) models of transcription factor motifs.TFT analysis can be performed on gene target sets derived from Ch IP-Seq (yellow) or transcriptomics data (red).Gene promoter annotation in combination with network analysis and sequence-resolution of enriched transcriptional motifs in epigenomic data reveals transcription factor families that act synergistically with epigenomic master regulators.By investigating complementary omics levels, a close teamwork of the transcriptional and epigenomic machinery was discovered.The intersection of analysis of motif enrichment (AME) and transcription factor target (TFT), and upstream regulator analysis (URA) approaches provides insights into cooperative networks of transcription factors associated with epigenomic regulators.Importantly, such genome-wide information can be accessed at the sequence or gene level providing different level of depth and resolution.
a By conjoining epigenomics and transcriptomics data, it is possible to define an effector network comprised of target genes affected by epigenomic regulation.
The discovered network is tightly connected and surrounds the histone lysine demethylase KDM3A, basic helix-loop-helix factors MYC, HIF1A, and SREBF1, as well as differentiation factors AP1, MYOD1, SP1, MEIS1, ZEB1, and ELK1.
In such a cooperative network, one component opens the chromatin, another one recognizes gene-specific DNA motifs, others scaffold between histones, cofactors, and the transcriptional complex.
In cancer, due to the ability to team up with transcription factors, epigenetic factors concert mitogenic and metabolic gene networks, claiming the role of a cancer master regulators or epioncogenes.
Significantly, specific histone modification patterns are commonly associated with open or closed chromatin states, and are linked to distinct biological outcomes by transcriptional activation or repression.