Singh Group

Research Projects:

Gene regulatory networks that dictate cell fate choices in the immune system (Project I)

Our long-standing interest in the regulation of cell fate choices in the immune and hematopoietic systems was initiated by our genetic analysis of the transcription factor PU.1, a member of the Ets super-family. We demonstrated that PU.1 was specifically required for the development of both the innate (macrophages and granulocytes) as well as the adaptive (B and T lymphocytes) lineages of the immune system. Importantly, PU.1 was suggested to function in a cell-intrinsic manner at the level of multipotential lymphoid-myeloid progenitors. Recently, hematopoietic intermediates that can generate macrophages, granulocytes as well as lymphocytes but lack erythrocytic and megakaryocytic developmental potentials have been characterized by other laboratories leading to a revised developmental framework for hematopoiesis.

We are analyzing the molecular mechanisms by which PU.1 regulates cell fate choice in the context of macrophages and neutrophils. We have elucidated a novel regulatory circuit comprised of counter antagonistic repressors Egr/Nab and Gfi-1, which function to resolve an initial mixed lineage pattern of gene expression into one that is specific for macrophages or neutrophils. Importantly, the experimental results have been used to assemble and mathematically model a gene regulatory network that exhibits both graded and bistable behaviors and more generally accounts for the onset and resolution of mixed lineage patterns during cell fate determination (collaboration with A. Dinner).

We are currently utilizing a combination of genetic, molecular and mathematical modeling approaches to assemble and analyze gene regulatory networks orchestrating cell fate choices in the hematopoietic system. These include: ChIP-on-Chip to connect each transcription factor in a given network with its large set of target genes and high throughput functional screens of lineage- and stage-specific cis-regulatory elements.

See also:

>> Regulation of discrete developmental transitions within the B-cell developmental pathway (Project II)

>> Nuclear compartmentalization, transcription and recombination dynamics of immunoglobulin loci (Project III)

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