Research Project 1: RNA Polymerase II CTD-Mediated Transcription Regulation
A central focus of our research is to elucidate the fundamental principles of transcriptional regulation. The transcription of genetic information into mature RNA messages relies on a dynamic transcription apparatus, composed of RNA polymerase II (Pol II) and various processing factors. The proper assembly of this apparatus is governed by the C-terminal domain (CTD) of Pol II, which encodes regulatory information through a mechanism known as the “CTD code.” This code operates via conformational changes in the CTD, driven primarily by alterations in its phosphorylation state. Our research aims to uncover how CTD phosphorylation is regulated, how it influences transcriptional outcomes, and how these processes contribute to critical biological phenomena, such as cancer and neurogenesis.
- Phosphorylation Dynamics of the CTD
During each transcription cycle, the CTD is phosphorylated at Ser2 and Ser5 residues. While Tyr1, Thr4, and Ser7 are also phosphorylated, their roles in transcription remain poorly understood. We are actively investigating the functional significance of these understudied phosphorylation events. - Decoding Combinatorial Phosphorylation Patterns
The combinatorial phosphorylation of the CTD generates precise regulatory codes that orchestrate transcriptional events. Using a unique biochemical approach, we aim to decode these complex phosphorylation patterns and their impact on transcription.
Research Project 2: Structure-Based Drug Design for Alzheimer’s Disease and Glioblastoma
Leveraging our extensive expertise in kinases and phosphatases, we employ structure-based approaches to design inhibitors targeting a neuronal pathway regulated by the transcription factor REST (RE1-Silencing Transcription Factor). Dysregulation of this pathway is implicated in neurological disorders such as Alzheimer’s disease and glioblastoma. While transcription factors like REST are traditionally challenging to target with small molecules, our strategy focuses on modulating the pathway by controlling the stability of REST. A major focus of our work is targeting the SCP/FCP phosphatase family, which plays a critical role in regulating REST and its associated pathways. By designing small-molecule compounds that selectively inhibit or modulate these phosphatases, we aim to develop novel therapeutic strategies for these devastating diseases.
Research Project 3: Protein Engineering Guided by Structure, Directed Evolution, and AI Design
The University of Texas at Austin is home to a world-renowned engineering school, and we actively collaborate with experts in chemical and bioengineering to advance protein engineering. In a recent partnership with the Alper and Ellington labs, we have integrated artificial intelligence (AI) with rational structural design to optimize protein functions for applications such as plastic degradation and transcription regulation. Additionally, a long-standing collaboration between our lab and Dr. George Georgiou’s group leverages cutting-edge protein engineering techniques to develop a new generation of non-immunogenic, pharmacologically optimized enzymes. These enzymes are designed for amino acid depletion therapies, offering innovative approaches to chemotherapy for central nervous system (CNS) cancers.
