Mitchell Grinwald

MSTP in PhD Training

Program: Molecular Genetics and Genomics

Current advisor: Ting Wang, PhD

Undergraduate university: Washington University, 2020

Enrollment year: 2021

Research summary
Defining the Role of Polycomb Repressive Complex 2 in Regulating Transposable Element Activation in Diffuse Midline Glioma and Malignant Peripheral Nerve Sheath Tumor

Transposable elements (TEs) are silenced by DNA methylation in somatic tissues but are dysregulated in patient tumors. Activated TEs can drive the formation of tumor-specific transcripts, which provide abundant opportunities for the development of gene and immunotherapies. Recent studies have linked PRC2-inactivating mutations to increased TE expression in human tumors, and PRC2-inhibiting drugs can drive ERV and LINE1 expression, accompanied by an interferon response in a variety of cancers. In Diffuse Midline Glioma (DMG) and Malignant Peripheral Nerve Sheath Tumor (MPNST), mutations that disrupt PRC2 function are highly recurrent and prognostically significant. I hypothesize that integrating PRC2 into existing models of tumor TE regulation will help define novel disease-specific TE therapeutic targets.
I analyzed Publicly available RNA-Seq data from 17 DMG and 41 MPNST patients to define TE subfamily and locus-specific transcription using TEtranscripts and TElocal. Additionally, TE-promoters and tumor-specific TE transcripts (TS-TETs) were identified across diseases and PRC2 mutation groups using TEProf3. PRC2-inhibiting mutations were associated with increased TE transcription across both tumor types. 10 previously discovered tumor-specific TS-TETs were identified in the MPNST samples, while 6 such TS-TETs were found in the DMG group. Several of these candidates were predicted to produce novel proteins, resulting in tumor-specific antigens. Follow-up experiments will establish the mechanism by which PRC2 regulates TEs in DMG and MPNST, while in vitro experiments will lay the groundwork for targeting TE-derived therapeutic vulnerabilities in these devastating diseases.

Graduate publications