Danfeng

Cai

, PhD

The Cai lab focuses on understanding how the transcription process is regulated in normal and cancer cells. We are intrigued by the discoveries in our lab that many transcription factors involved in cancers can form small, liquid-like condensates in the nucleus to activate transcription. Our results are consistent with an emerging and paradigm-shifting view in biology: many biochemical reactions inside the living cell are organized in liquid-like condensates formed by weak protein and nucleic acid interactions. This implies that the material states as well as the components of cellular assemblies matter for their functions. We develop and employ many cutting-edge imaging tools in the lab, such as super resolution microscopy, single particle tracking, and optogenetics. By studying these condensates, we hope to understand how transcription is differentially organized in normal and cancer cells, and how we can target these condensates for cancer therapies.

There are two main research directions in the Cai lab:

Characterization of transcription condensates formed by YAP/TEAD

Every aspect of human function, from cell differentiation in development to normal cell maintenance, requires precise activation of transcription. While transcription can happen in many places in the genome, transcription of genes that maintain cell identity and function frequently happens in transcription hubs (or condensates), where high transcriptional activity is seen. Dysregulation of transcription hubs is linked with many diseases such as neurodegeneration and cancer. Due to their importance in cell function and diseases, there is growing interest to study transcription hubs. However, many questions remain, and the most pressing ones are: 1) how do transcription hubs form inside the nucleus? And 2) how do transcription hubs activate transcription? Our laboratory is uniquely positioned to answer these two essential questions, using the powerful Yes-associated Protein (YAP) transcription hub system developed in Dr. Cai’s postdoctoral work. We have discovered that Yes-associated protein (YAP), a transcription coactivator and important oncoprotein, forms liquid-like condensates in the nucleus to activate transcription. We will continue to investigate the pathways regulating YAP condensate formation, and how these condensates influence local chromatin structure and transcriptional activity. We will use a cutting-edge super resolution technique to visualize accessible chromatin domain changes during YAP condensate formation, and live-cell imaging to observe YAP downstream transcription changes. Our study will have implications for future cancer therapies, as YAP is over-expressed in many cancers, and YAP condensates in cancer cells are linked with malignancy.

Roles of membrane-less organelles in Renal Cell Carcinoma

Papillary renal-cell carcinoma (PRCC) is the second most common kidney cancer in America. Despite the risk and prevalence of PRCC, its etiology remains unclear. One of the most prominent cellular features of PRCC is the presence of membrane-less organelles (MLOs). MLOs form by the physicochemical process of phase separation, in which weak, multivalent interactions drive the associated macromolecular components to form a dense liquid-like assembly. Although it is well-known that the presence of MLOs correlate with more malignant grades of PRCC, a largely unanswered question is how these MLOs form and function in PRCC. There is great value in understanding the basic biology of MLOs in PRCC, that ultimately will be useful in designing novel PRCC drugs targeting these MLOs. We will 1) conduct basic biology research to better understand etiology and cancer progression of kidney cancer; and 2) define the biology of rare kidney cancers and develop treatments to improve outcomes and reduce death. By designing novel imaging and proteomics-based tools, we will investigate how MLOs form and function in PRCC. We hypothesize that MLOs in PRCC form through weak multivalent interactions among their components, and function by concentrating specific protein factors to buffer cellular protein concentration or activating transcription.