Sci. Adv.|Xu Liang/Chen Ye/Huang Yulun collaborated to reveal the active chromatin map of glioblastoma

Editor | Glioblastoma (GBM) is a primary intracranial malignant tumor with high heterogeneity and poor prognosis.

At present, GBM genomics research has revealed a series of gene mutations related to the occurrence and development of GBM, and suggested that there are cancer-promoting mechanisms other than gene mutations.

Decoding the epigenetic regulation of GBM will help us understand the disease characteristics and pathological mechanisms of GBM.

Recently, Dr.
Xu Liang and Dr.
Chen Ye from the H.
Phillip Koeffler research group of the National University of Singapore joined forces with Dr.
Huang Yulun from the Dushu Lake Hospital affiliated to Soochow University, Dr.
Tuan Zea Tan from the Institute of Cancer Science of Singapore, and the Carol Tang Group of the National Institute of Neuroscience of Singapore.
Published a research paper titled Topography of transcriptionally active chromatin in glioblastoma in Science Advances.

The study systematically analyzed the histone H3K27ac modification profiles in GBM clinical specimens (95 cases), control brain tissue samples (12 cases), and GBM cell lines, and further combined with transcriptome data to define GBM and control brain tissues The active cis-acting elements and core transcriptional regulatory network.

The study not only found significant differences between GBM and control brain tissue in terms of active transcriptional regulatory elements, especially super enhancer regulation, but also revealed the tumor heterogeneity and transcription diversity of GBM from the enhancer level.

According to the H3K27ac signal captured in the tissue and the inherent gene expression profile of GBM cells, GBM can be divided into four molecular subtypes, including AC1-mesenchymal, AC1-classical, AC2-proneural and AC3-proneural.

GBM specimens of different subtypes have significant differences in tumor microenvironment, immune cell infiltration, genetic mutations, signaling pathways, and core transcriptional regulatory loops.

Therefore, this discovery can provide a new idea for optimizing GBM cancer classification.

In addition, by analyzing cancer-specific enhancer signals, the study discovered and identified a series of transcription factors, long non-coding RNAs and drug targets (such as MNK2 and BRD4, etc.
) driven by GBM-specific super enhancers.

The researchers further used GBM cell lines, patient-derived tumor stem cells, and orthotopic xenograft tumor models to systematically validate the functions of several newly discovered cancer-promoting factors.

At the same time, based on the transcription factor expression profile driven by the super enhancer, the study also constructed a GBM risk assessment and prognostic analysis model.

This model has shown ideal performance in multiple independent glioma cohorts, suggesting positive clinical significance and transformation potential.

The results of this article serve as the team’s recent advances in cancer transcription regulation (PNAS, 2017; PNAS, 2018; Nucleic Acids Res.
, 2018; Oncogene, 2021) and targeted intervention (Nat.
Commun.
, 2019; Oncogene, 2020) and other fields The further extension of the work provides important data support and theoretical basis for the in-depth exploration of the pathogenesis and treatment strategies of GBM, and also provides valuable references and research clues for the research of other major diseases.

Dr.
Xu Liang, the first and lead contact author of this article, is currently employed by the School of Life Sciences of Zhejiang University as a researcher of the "Hundred Talents Program" and is setting up an independent laboratory.

Dr.
Xu Liang graduated from Zhejiang University with a bachelor’s degree, and later received a Ph.
D.
from the National University of Singapore (2015), and received research training in the Phillip Koeffler Laboratory of the Singapore Institute of Cancer Science and the Markus Muschen Laboratory of the City of Hope Comprehensive Cancer Center in the United States.
Served as a research scientist at the Singapore Institute of Cancer Science.

Dr.
Xu Liang has accumulated rich experience and achievements in cancer genetics, cancer biology and experimental therapeutics; the research team will combine molecular and cell biology, epigenetics and chemical biology and other research methods to analyze cell malignancy Transformation and genetic changes in the development of cancer, and explore intervention strategies.

Sincerely invite postdoctoral fellows and research assistants with a background in biology and bioinformatics related disciplines to join the team and grow together.

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