Abstract A2-54: DNA methylation-dependent transcription regulatory networks elucidate dynamics of transcription regulatory circuitry in cancers

Abstract

Abstract Context-dependent DNA methylation plays a critical role in regulating gene transcription, thereby serving as an important epigenetic marker or regulator in many biological activities such as pluripotency, development, and complex diseases such as cancer. However, previously in most of the de novo reconstructions of cancer type-specific transcription regulatory networks (TRN), DNA methylation has rarely been taken into account as a significant factor in regulating transcription factor activity and controlling gene expression. The present study was set to systematically assess the involvement of DNA methylation in transcription regulatory circuitry in cancer. We took advantages of the multi-dimensional profiling data of DNA methylations and gene expressions in tumor samples of different cancers in The Cancer Genome Atlas (TCGA) consortium, and developed an integrative analysis pipeline based on conditional mutual information theory, to quantify the cooperative regulatory effects of CpG site methylations and transcription factors on gene expressions, in a genome-wide scale. Our analysis showed that DNA methylation and transcription factors indeed control gene expressions often in duet. To map the interplay between these two major defining factors of gene expression, DNA Methylation-dependent Transcription Regulatory Network (MeTRN), the first of its kind, was assembled for each of 19 major cancer types in TCGA. MeTRN provides a comprehensive view specifically on DNA methylation-dependent transcription events in each cancer type, and has been largely validated by public ChIP-seq and DNaseI-seq data. Comparison of these networks across cancer types showed that context-specificity of transcriptional circuits can be largely attributed to the context-dependent nature of DNA methylation patterns. Therefore, by assembling the cooperative effects of transcription factors and DNA methylations on gene transcription, MeTRN recapitulates an epigenetic scheme that implements dynamics of transcription regulatory circuitry across cancers via context-dependent DNA methylation marks. Supported by extensive cross-validations and experimental evidence, this epigenetically marked and dynamic transcription regulatory circuitry serves as a new basis for further mechanistic studies of gene expression dysregulations in cancers. Citation Format: Yu Liu, Yang Liu, Zhengtao Xiao, Xuerui Yang. DNA methylation-dependent transcription regulatory networks elucidate dynamics of transcription regulatory circuitry in cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-54.