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Enhancer methylation dynamics drive core transcriptional regulatory circuitry in pan-cancer

Oncogene volume 41, pages 3474–3484 (2022)Cite this article

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Abstract

Accumulating evidence has demonstrated that enhancer methylation has strong and dynamic regulatory effects on gene expression. Some transcription factors (TFs) can auto- and cross-regulate in a feed-forward manner, and cooperate with their enhancers to form core transcriptional regulatory circuitries (CRCs). However, the elaborated regulatory mechanism between enhancer methylation and CRC remains the tip of the iceberg. Here, we revealed that DNA methylation could drive the tissue-specific enhancer basal transcription and target gene expression in human cancers. By integrating methylome, transcriptome, and 3D genomic data, we identified enhancer methylation triplets (enhancer methylation-enhancer transcription-target gene expression) and dissected potential regulatory patterns within them. Moreover, we observed that cancer-specific core TFs regulated by enhancers were able to shape their enhancer methylation forming the enhancer methylation-driven CRCs (emCRCs). Further parsing of clinical implications showed rewired emCRCs could serve as druggable targets and prognostic risk markers. In summary, the integrative analysis of enhancer methylation regulome would facilitate portraying the cancer epigenomics landscape and developing the epigenetic anti-cancer approaches.

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Fig. 1: Overview of enhancer transcription and methylation in human cancers.
Fig. 2: Global activation of enhancer by hypomethylation in cancer samples.
Fig. 3: Inferring regulatory patterns dominated by enhancer methylation in cancers.
Fig. 4: TF is involved in enhancer methylation regulation.
Fig. 5: The potential clinical utility of emCRCs.

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Data availability

All the data used in the analysis can be obtained from TCGA, ENCODE, and GEO.

Code availability

The data analysis in this manuscript was conducted using custom scripts, all available at http://bio-bigdata.tech/EmethCRC.

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Acknowledgements

The authors gratefully thank the TCGA, ENCODE, TANRIC, and GEO for providing data for this work.

Funding

This work was supported by the Natural Science Foundation of Heilongjiang Province, China [LH2020C05]; the National Natural Science Foundation of China [32170674 and 32070672].

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  1. These authors contributed equally: Xu Pan, Xin Li.

Authors and Affiliations

  1. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China

    Xu Pan, Xin Li, Jie Sun, Zhiying Xiong, Haoyu Hu, Shangwei Ning & Hui Zhi

  2. Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Xin Li

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Contributions

XP designed the study, performed analysis, wrote and revised the manuscript. XL constructed the webserver and revised the manuscript. HH helped with data collection. JS and ZX proofread the manuscript and linguistic touch-ups. HZ and SN share the senior authorship of this study. The authors read and approved the final manuscript.

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Correspondence to Shangwei Ning or Hui Zhi.

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Pan, X., Li, X., Sun, J. et al. Enhancer methylation dynamics drive core transcriptional regulatory circuitry in pan-cancer. Oncogene 41, 3474–3484 (2022). https://doi.org/10.1038/s41388-022-02359-x

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