Research

Gene regulation plays a fundamental role in cellular development and cancer. Our lab uses genomics and systems biology approaches to understand the gene regulatory factors underlying cellular processes. We take snapshots of the regulatory systems using bulk and single-cell omics and imaging assays, and develop computational algorithms to integrate data and generate testable models of gene regulatory pathways in model systems.

Understanding the molecular basis of therapeutic resistance in cancer

We have a number of ongoing projects investigating the molecular basis of oncogenesis and therapy resistance in cancer cells. Some highlights are:

1) Generation of a bulk and single-cell multi-omic atlas of pediatric cancer at multiple therapeutic time points
2) Identification of novel combination therapies by understanding disease-perturbed gene networks
3) Understanding the cellular adaptations of cancer cells to targeted therapy and immunotherapy through novel systems biology approaches

Unraveling the gene regulatory factors involved in cellular development

We are studying gene regulatory networks controlling the embryonic origin of hematopoietic stem cells, differentiation of T-cells, and pediatric cancers. Specific questions we ask include:

1) What are the key regulators and cis-regulatory elements that control cell/tissue-specific gene expression in these systems?
2) How does the 3-dimensional genome organization controls cell/tissue-specific gene expression in these systems?
3) What are the mutations in the cis-regulatory DNA sequences that confer disease risk in these systems?
4) What are the signaling pathways that mediate cell-cell communications in in these systems?

Development of computational methods to interpret high-dimensional and single-cell transcriptomics, proteomics, and epigenomics data

We develop data-driven methods to integrate multi-omics data using network biology and principled machine learning. We generate large data sources using methods such as bulk and single-cell RNA-Seq, ATAC-Seq, Hi-C, and multiplexed fluorescent imaging. We develop computational methods to integrate these data sources and model the gene regulatory architecture that underlies cellular fate and disease. Ongoing projects include:

1) Development of network-based approaches to identify disease-perturbed pathways and critical regulatory nodes for the diagnosis and prognosis of diseases, and to identify candidates for novel therapeutics
2) Integration of single-cell transcriptomics and epigenomics to characterize the sequence of gene regulatory events leading to cellular differentiation and cancer
3) Understanding the impact of non-coding somatic variation, including copy number alterations and structural variation, in pediatric cancer

We gratefully acknowledge support from the following funding agencies for our ongoing projects:

NIH/NICHD, R01 HD089245
Mechanisms of endothelial-to-hemogenic transition mediated by Runx1

NIH/NIGMS, R01 GM108716
Computational methods for unraveling combinatorial gene regulation

NIH/NIGMS, R01 GM104369
A toolkit for identifying causal variants in transcriptional enhancers

NIH/NIAAA, R01 AA024486
A systems approach to the genetic study of alchohol dependence

NIH/NCI, U01 CA226187
Tools for annotating mutations in the 3D cancer genome

NIH/NCI, U2C CA233285
Center for pediatric tumor cell atlas

NIH/NCI, U01 CA232361
Defining and overcoming intrinsic T cell dysfunction to enable pediatric
immunotherapy

The Lenona M & Harry B. Helmsley Charitable Trust, #2008-04062
A Crohn’s disease epithelial stem cell atlas: pediatric to adult continuum

Alex’s Lemonade Stand Foundation
Single cell profiling of early T cell precursor acute lymphoblastic
leukemia