Positions

Assistant Professor
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX, US
Member
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas, United States
Member
Center for Drug Discovery
Baylor College of Medicine
Member
Computational and Integrative Biomedical Research Center
Baylor College of Medicine

Education

Postdoctoral Fellowship at Dana-Farber Cancer Institute
PhD from Massachusetts Institute of Technology
Computational and systems biology
BS from Duke University

Professional Interests

  • Targeting chromatin and transcription deregulation in cancer

Professional Statement

Cancer is fundamentally a disease of altered gene regulation. Practical therapeutic strategies require an understanding of the complex transcriptional mechanisms driving tumorigenesis. Our laboratory applies computational, molecular, and chemical biology to understand how gene regulation and downstream pathways are altered in cancer. Perturbations to chromatin and transcriptional regulators that control gene expression occur frequently in cancer, as exemplified by the MYC transcription factor oncogene, which is the most commonly amplified gene in cancer. We are further motivated to better understand mechanisms of transcriptional deregulation by recent observations that drugs targeting chromatin and transcription regulators can have selective effects on oncogene transcription and tumor proliferation. As these compounds enter our clinical armamentarium, it is imperative to understand both the transcriptional mechanisms underlying oncogenic deregulation, and the consequences of direct pharmacologic targeting of chromatin and transcriptional regulators.

Guided by these objectives, our laboratory’s research is focused along three aims: 1) to develop novel computational and experimental approaches to map global and dynamic changes in chromatin and transcription during tumorigenesis, 2) to uncover novel transcriptional mechanisms of tumorigenesis through the discovery and mechanistic characterization of new chemical probes, and 3) to utilize enhancer and chromatin profiling to classify tumor cell identity and discover new tumor dependencies.

In prior work, we have studied MYC deregulation in cancer and have found that oncogenic MYC invades active regulatory elements across the entire genome resulting in increased transcription at all active genes, thereby amplifying a tumor cell’s pre-existing gene expression program. MYC deregulation itself often involves the formation of large enhancer elements upstream of the MYC gene where chromatin and transcriptional regulators localize disproportionately. These large “super-enhancers” are found at other oncogenes in many tumors, suggesting a common mechanism for oncogene activation. General inhibition of chromatin regulators using small molecule chemical probes selectively disrupts super-enhancer driven oncogenes, and in the case of MYC, abrogates MYC induced transcriptional amplification. In addition to chemical targeting of super-enhancers, we have found that super-enhancer profiling in poorly characterized tumors provides a map of tumor specific oncogenes. Here, computational modeling of enhancers and super-enhancers enables a reconstruction of the master transcription factors that form tumor specific gene regulatory networks and establish tumor cell identity. This approach has allowed us to infer and predict tumor cells of origin of individual medulloblastoma subgroups, and to identify critical regulators of medulloblastoma subgroup identity.

To continue this work, our laboratory is assembling a collaborative team of interdisciplinary scientists to address new challenges at the intersection of computer science, cancer biology, and therapeutics. Our mission is to train young scientists and to exemplify the principles of open source discovery to advance our understanding of transcriptional control in cancer and accelerate therapeutic development.

Selected Publications

Funding

CPRIT Scholar for Cancer Research
Cancer Prevention Research Institute of Texas (CPRIT)