Primary AppointmentBiochemistry and Molecular Genetics
Contact InformationEmail: firstname.lastname@example.org
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 molecules to combat these diseases based on these mechanisms. 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 (Jiang et al, Cell 2011), hematopoietic (Yang et al., Blood 2014; Yang et al., JEM 2016), and neural (Shah et al., JMCB 2019) 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? (Yang et al., JCI 2018). 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 (or biomolecular condensation), a fundamental principle in organizing intracellular space and biochemistry. Our previous work (Jiang et al., Nat Struct Mol Biol 2013) has identified AKAP95, a nuclear zinc-finger protein, as a remarkable transcription co-activator. We have recently shown that AKAP95 is also an RNA-binding protein and regulates alternative pre-mRNA splicing by direct interaction with pre-mRNA and hnRNP proteins (Hu et al., Nat Comm 2016). We now show that AKAP95 is associated with human cancer and that its activity in gene regulation is important for tumorigenesis through promoting cell proliferation and overcoming senescence. We have found that AKAP95 forms phase-separated and liquid-like condensates in vitro and in nucleus. Mutations of key residues to different amino acids perturb AKAP95 condensation in opposite directions. Importantly, the activity of AKAP95 in splice regulation is abolished by disruption of condensation, significantly impaired by hardening of condensates, and regained by substituting its condensation-mediating region with other condensation-mediating regions from irrelevant proteins. Moreover, the abilities of AKAP95 in regulating gene expression and promoting tumorigenesis require AKAP95 to form condensates with proper liquidity and dynamicity. These results thus link phase separation to tumorigenesis and uncover an important role of appropriate material properties (fluidity and dynamicity) of protein condensates in gene regulation and cancer. Our findings will most likely be applicable to other key regulators for gene expression, and may open new avenue of cancer treatment by targeting the condensation properties of those proteins. Phase separation regulates a very diverse range of cellular processes. In addition to our continued research on how AKAP95 phase separation regulates its molecular activity, we are also working on several other proteins that regulate gene expression and cancer. Currently, our research is funded by the NIH, DoD, American Society of Hematology, American Cancer Society, and Leukemia & Lymphoma Society.