Research interests
A Multi-Scale Analysis of Cell fate Commitment and Reprogramming
How are pluripotent Stem Cells “programmed” to generate all bodily cell types during development, and how can somatic cells be “reprogrammed” to an ESC-like state? To delineate the events that drive cell fate decisions we use genomic and single cell approaches to identify markers and cell type specific signatures that can distinguish cell states and the regulatory mechanisms that govern the production of such diversity. By applying innovative technologies, we create detailed atlases of regulatory DNA and characterize novel chromatin states and their function in the establishment and maintenance of cell identity. We aim to understand the impact of chromatin reprogramming on cell fate commitment in normal development and during initiation and cancer progression.
Mechanism of Transcription factor assembly and binding dynamics in gene regulation
Activation and repression of developmental gene expression programs are controlled by the combinatorial actions of sequence specific transcription factors (TFs) and their effects on 3D genome organization. Yet, how TFs identify and select their genomic targets from thousands of potential binding sites remains unclear. We are assessing the contribution of DNA sequence variation, chromatin content, RNA presence and modalities of TF interactions on genomic target selection. Current research in the lab is aimed at understanding how reprogramming transcription factors facilitate the loss or destabilization of somatic cell identities by repressing diverse somatic gene regulatory programs and how these pathways potentially contribute to malignancies that involve de-differentiation of somatic tissues.
Engineering customized Hematopoietic Stem, Progenitor and Mature Blood cells
Hematopoietic Stem Cells (HSCs) represent a rare cell type capable of reconstituting all blood lineages, and through transplantation the only curative therapy for the treatment of blood disorders. In vitro generation of clinically relevant blood progenitors holds great promise for regenerative medicine and makes disease modeling, toxicity screening, and immunotherapy tangible. Significant challenges in HSC expansion and failure to differentiate HSCs from pluripotent stem cells in vitro, makes direct conversion of somatic cells to HSCs (iHSCs) and/or their differentiated descendants into an attractive approach. We use novel computational and systems biology approaches to define and manipulate key cis regulatory elements that contribute to HSC specification and the factors that contribute to differentiation towards lymphoid lineages.
Novel tools to study Epigenetic regulation, Chromatin architecture, and TF dynamics
While traditional transcriptomic, epigenetic, and proteomic profiling methods have provided key insights in gene regulation, chromatin structure and protein function they typically rely on large populations of cells, are largely correlative, and fail to capture dynamic transitions in a direct manner. We are developing novel co-assays that measure protein binding and transcriptional output within single cells of heterogeneous populations to measure in a quantitative manner the causal relationships between transcription factor binding and gene regulation.