Professor, Biochemistry and Molecular Genetics
- BS, , Tsinghua University
- PhD, , Johns Hopkins School of Medicine
- Postdoc, , Rockefeller University
Biochemistry, Bioinformatics and Genomics, Cancer Biology, Development, Epigenetics, Genetics, Metabolism, Molecular Biology, Stem Cells & Regeneration
Regulation of stem cell function and tumorigenesis by epigenetics and biomolecular condensation (phase separation)
The broad interest of the Jiang lab is how gene regulation at the chromatin, transcriptional, and post-transcriptional levels controls the stability and plasticity of cell identity, how dysregulation of these mechanisms lead to diseases especially cancer, and how we may develop novel strategies to combat these diseases based on these mechanisms. In particular, we are studying how epigenetic mechanisms and liquid-liquid phase separation regulate stem cell function and tumorigenesis.
We have been studying the functional role of efficient H3K4 methylation in regulating stem cell fate determination and tumorigenesis. We have shown that Dpy30, one of the core subunits of the Set1/Mll family of H3K4 methyltransferases, plays an important role in the fate determination of embryonic, hematopoietic, and neural stem cells. Our recent work has shown that H3K4 methylation governs two fundamental cellular processes, energy metabolism and DNA damage response at the chromatin level in support of the mission of stem cells in maintaining tissue homeostasis.
Moreover, our recent studies using our genetically engineered mouse model strongly suggest that cancer cells hijack this epigenetic modulator to drive a gene expression program supporting tumorigenesis, meanwhile creating “epigenetic vulnerability”. We are currently studying the molecular mechanisms underlying such epigenetic vulnerability and also developing pharmacologic intervention strategies to target this modulator for potential cancer treatment. As a proof-of-principle, we have developed Dpy30-inhibitory peptides that suppress and sensitize MYC-dependent blood cancers.
In a new research direction the lab has taken recently, we have become extremely interested in how disease such as cancer is controlled by the spatiotemporal regulation of gene expression through liquid-liquid phase separation, which is emerging as a fundamental principle in organizing intracellular biochemistry and often drives the formation of biomolecular condensates.
We have identified AKAP95 as a novel protein that associates with Dpy30, enhances the histone methylation activity, and co-activates transcription. These results provide novel insight into how epigenetic modifications and transcription are regulated. My lab has later shown that AKAP95 regulates splicing by direct interactions with pre-mRNA and RNA-processing factors. We then discovered an important role for AKAP95 in promoting tumorigenesis. Mechanistically, AKAP95 forms phase-separated condensates, and the proper fluidity and dynamicity of the condensates are crucial for the abilities of AKAP95 in regulation gene expression and tumorigenesis. This is one of the early studies to directly show a critical role of biomolecular condensation in cancer, and the first study to demonstrate that material properties of the condensates are important for gene control and cancer. In a more recent work, we have shown that UTX/KDM6A, a chromatin regulator frequently mutated in human cancers, suppresses cancer (including leukemia) through its phase separation property, which enriches key histone modification activities in the condensates and controls the leukemia gene expression programs through multiple-levels of chromatin functions.
Phase separation regulates a very diverse range of cellular processes. In addition to our continued research on how AKAP95 and UTX phase separation regulates their molecular activities, we are also working on several other nuclear proteins that may regulate the process of gene expression through their phase separation property.
Currently, our research is funded by the NIH, DoD, and Leukemia & Lymphoma Society.