How a cell decides its lineage fate is a long-standing and enigmatic question in biology. Our multi-disciplinary research aims to decipher the cell autonomous gene regulatory mechanisms and non-autonomous cell communication mechanisms that drive cellular lineage decisions in development, and the dysregulation of these mechanisms in cancer.  We investigate these questions in close collaborative partnerships.  

Computational methods to infer lineage decision mechanisms

High throughput single-cell genomics technologies have revolutionized the study of developmental and disease trajectories, offering an unprecedented scale and resolution. We employ cutting-edge analysis tools and develop novel machine learning methods to leverage these technologies and better characterize mechanisms driving these trajectories. We design our analysis approaches with a deep appreciation for the underlying biology to recapitulate developmental processes and derive novel mechanistic insights about the system. As an example, modeling of cell-fate choices as a continuous phenomenon enabled us to pin-point timing of lineage decisions and identify unexpected lineage transitions during mammalian endoderm development.

See Nature article: The emergent landscape of the mouse gut endoderm at single-cell resolution.

Cell autonomous gene regulatory networks are the primary drivers of lineage decisions in developmental trajectories. We are developing methods to integrate multiple single-cell modalities to infer the regulatory network reconfigurations that drive cell state transitions and cell-fate choices along trajectories. Gene regulatory networks invariably are downstream of  cell communication and signaling mechanisms. We are developing algorithms to model cell-cell communication and how they shape developmental trajectories. Spatial organization of cells in tissues can often times be derived from single-cell RNA-seq but we also aim to employ the emerging and exciting advances in spatial transcriptomic technologies to understand how cell communication can shape lineage decisions. 

Mutations in regulators have been demonstrated to be key drivers in many cancers. As with development, cell communication with the microenvironment also plays a central role in disease progression. We are interested in using the developmental / healthy system as a reference and develop methods to understand the disruption and dysregulation of these mechanisms in disease initiation, progression and transformation.

Disruption of developmental mechanisms in disease

We are strongly committed to open and reproducible science. We strive to ensure that the methods we develop can be widely used by the scientific community. All of our algorithms are available as open-source software packages through the Resources page and are accompanied by clear documentation and use cases.