Wang, Shu-Ping - IBMS, Sinica

REASEARCH INTERESTS & GOALS

My lab’s long-term research interest is to elucidate epigenetic regulatory mechanisms related to the fundamental biological issues, including developmental defect and cancer. The research focus is to decipher how the key epigenetic regulators, including histone lysine methyltransferases (HMTs) and demethylases, control target gene transcription through enhancer landscape modifications under physiological and disease conditions. With all the proposed research programs, our final goal is to utilize the CRISPR-based epigenome editing technology and/or small molecule inducers/inhibitors to precisely manipulate gene expression programs that can determine cell type specification or correct misregulated gene expressions in cancer diseases.

RESEARCH DIRECTIONS & PROJECTS

Targeting H3K4 HMTs Mixed Lineage Leukemia 3/4 (MLL3/4) in human cancers

Although the cancer genome sequencing data support a key tumor suppressor role of MLL3 or MLL4 in a number of human cancers, there are certain cases in which these histone-modifying enzymes may function as oncogenic cofactors in driving tumorigenesis. In this research theme, we would like to elucidate the potential MLL3/4 oncogenic functions in certain cancer types and identify small-molecular inhibitors of MLL3/4 as a potential targeted therapy for these cancers.

A H3K4 methyltransferase/demethylase axis regulates cancer progression

While H3K4 tri-methylation (H3K4me3) positively regulates gene transcription at promoters, recent studies indicated a potential role of H3K4me3 in enhancer activation. The KDM5C demethylase complex functions to maintain the enhancer activity at normal levels for majority of individual and super enhancers, whereas deficiency in this H3K4 demethylase complex can increase the levels of enhancer-associated H3K4me3 and upregulate enhancer activities, leading to oncogene activation and cancer progression. In this project, we would like to identify the key H3K4 HMT(s) responsible for enhancer-associated H3K4me3 and elucidate the underlying mechanism of the novel H3K4 methyltransferase/ demethylase axis functions in cancer progression.

Mapping enhancer regulatory elements of oncogenes and tumor-suppressor genes

Enhancers contain various DNA sequecnes that are essential for precise gene regulation and can communicate with target promoters by forming looping structures. Importantly, enhancer malfunction can casue abnormal expression of target oncogenes or tumor suppressor genes, inducing tumorigenesis. Thus, a complete understaning of oncogene/tumor suppressor gene-associated enhancer sequences and genomic locations will benefit to the cancer epigenome profiling. In this research direction, we would like to set up a pipline for the identification and chracterization of key enhancers with their target genes in cancer epigenomes by ChIP-sequencing, CRISPR inteference (CRISPRi), and 4C (chromatin conformation caprture)-sequencing technologies.