Harinder Singh, PhD - Professor, Immunology, Director, Center for Systems Immunology

Gene regulatory networks orchestrating immune cell fate dynamics

Abstract

I have had long standing interest in the discovery and analysis of transcription factors (TFs) and gene regulatory networks (GRNs) which orchestrate the development and functioning of immune cells. We have shown that the Ets family member PU.1 is required for the development of innate and adaptive immune cell lineages and assembled and analyzed the gene regulatory networks within which it functions to induce the specification of alternate cell fates, B cells versus macrophages. Work on PU.1 led to the discovery and analysis of IRF4 and IRF8 that are immune-system specific members of the IRF family of transcriptions factors. They have crucial and diverse functions in regulating B and T lymphocytes as well as macrophages and dendritic cells. A notable structural finding has been the discovery of distinct types of composite regulatory elements in immune response genes that are cooperatively bound by IRF4 or IRF8 with PU.1 or the AP-1 member, BATF.  Currently we are coupling structural and functional genomics as well as computational analyses, to analyze coherent networks of transcription factors and the large sets of genomic regulatory sequences through which they act. This will enable the analysis of complex GRNs underlying the development and functioning of innate and adaptive immune cells in health and disease.