Integrative epigenomic analyses of small cell lung cancer cells demonstrates the clinical translational relevance of gene body methylation

Lorinc S Pongor; Camille Tlemsani; Fathi Elloumi; Yasuhiro Arakawa; Ukhyun Jo; Jacob M Gross; Sara Mosavarpour; Sudhir Varma; Rahul K Kollipara; Nitin Roper; Beverly A Teicher; Mirit I Aladjem; William Reinhold; Anish Thomas; John D Minna; Jane E Johnson; Yves Pommier

doi:10.1016/j.isci.2022.105338

Integrative epigenomic analyses of small cell lung cancer cells demonstrates the clinical translational relevance of gene body methylation

iScience. 2022 Oct 12;25(11):105338. doi: 10.1016/j.isci.2022.105338. eCollection 2022 Nov 18.

Authors

Lorinc S Pongor¹, Camille Tlemsani^{1

2}, Fathi Elloumi¹, Yasuhiro Arakawa¹, Ukhyun Jo¹, Jacob M Gross¹, Sara Mosavarpour¹, Sudhir Varma¹, Rahul K Kollipara³, Nitin Roper¹, Beverly A Teicher⁴, Mirit I Aladjem¹, William Reinhold¹, Anish Thomas¹, John D Minna⁵, Jane E Johnson⁶, Yves Pommier¹

Affiliations

¹ Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
² Department of Medical Oncology, INSERM U1016-CNRS UMR8104, Cochin Institute, Paris Cancer Institute CARPEM, Université Paris Cité, APHP Centre, 75014 Paris, France.
³ McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Developmental Therapeutics Program, DCTD, National Cancer Institute, Bethesda, MD 20892, USA.
⁵ Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Internal Medicine and Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Department of Neuroscience, Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.

Abstract

DNA methylation is a key regulator of gene expression and a clinical therapeutic predictor. We examined global DNA methylation beyond the generally used promoter areas in human small cell lung cancer (SCLC) and find that gene body methylation is a robust positive predictor of gene expression. Combining promoter and gene body methylation better predicts gene expression than promoter methylation alone including genes involved in the neuroendocrine classification of SCLC and the expression of therapeutically relevant genes including MGMT, SLFN11, and DLL3. Importantly, for super-enhancer (SE) covered genes such as NEUROD1 or MYC, using H3K27ac and NEUROD1, ASCL1, and POU2F3 ChIP-seq data, we show that genic methylation is inversely proportional to expression, thus providing a new approach to identify potential SE regulated genes involved in SCLC pathogenesis. To advance SCLC transitional research, these data are integrated into our web portal (https://discover.nci.nih.gov/SclcCellMinerCDB/) for open and easy access to basic and clinical investigators.

Keywords: Cancer; Cancer systems biology; Epigenetics.

Abstract

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