Harinder Singh, Ph.D.

  • Professor and Director
  • Center for Systems Immunology
  • Department of Immunology

Education & Training

  • Ph.D. Molecular Biology and Biochemistry, 1984, Northwestern University, U.S.A.
  • M.Sc. (Honors) Biochemistry, 1979, Punjab Agricultural University, India
  • B.Sc. (Honors) Biochemistry, 1977, Punjab Agricultural University, India

Research Interest Summary

Experimental and computational analyses of gene regulatory networks controlling immune effector and memory cell states

Research Categories

Research Interests

I have had long standing interests in the discovery of transcription factors (TFs) and analysis of gene regulatory networks (GRNs) that control the development and functioning of immune cells. As an HHMI Investigator at the University of Chicago, my lab discovered that the Ets family member PU.1 was required for the development of multiple myeloid and lymphoid lineages. We systematically illuminated the molecular functions of PU.1 in the development of B cells and macrophages. In a collaboration, we cloned IRF4, a PU.1 partner. IRF4 regulates plasma cell differentiation and its molecular actions are antagonized by the related protein IRF8 to promote the germinal center B cell fate. IRF4 and IRF8 are immune-system specific members of the IRF family of transcriptions factors that 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 the Ets family member PU.1 or the AP-1 member, BATF. We are using the toolkit of systems biology, including structural and functional genomics as well as computational modeling, to analyze coherent networks of transcription factors and the large sets of genomic regulatory sequences through which they act. This is enabling us to assemble GRNs underlying the development and activation of innate and adaptive immune cells with a focus on B cells as exemplars. The approaches are universal and are being extended to analyses of human immune cells in health and disease contexts. I have established a Center for Systems Immunology (CSI) that bridges faculty in Immunology and Computational and Systems Biology. The mission of the Center is to facilitate inter-disciplinary research collaborations focused on Systems Immunology by leveraging our expertise in high dimensional experimental approaches coupled with analytic pipelines and machine learning to enable biologically meaninful molecular patterns to be discovered in complex datasets. 

Representative Publications

Scott, E.W., Simon, M.C., Anastasi, J. and Singh, H. (1994) Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages.  Science 265:1573-1577.

DeKoter, R.P. and Singh, H. (2000) Regulation of B lymphocyte and macrophage development by graded expression of PU.1.  Science 288:1439-1441.

Laslo, P., Spooner, C.J., Warmflash, A., Lancki, D., Lee, H-J., Sciammas, R., Gantner, B., Dinner, A. and Singh, H. (2006) Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates. Cell 126:755-766.

Glasmacher E., Agrawal S., Chang A., Murphy, T.L., Zeng W., Vander Lugt B., Khan, A.A., Spooner C., Rutz S., Hackney J., Escalante C., Ouyang W., Littman, D., Murphy K.M. and Singh H. (2012) A genomic regulatory element that directs assembly and function of immune-specific AP-1/IRF complexes. Science 338:975-980; PMCID: PMC:5789805

Xu, H., Chaudhri, V.K., Wu, Z., Biliouris, K., Dienger-Stambaugh, K., Rochman, Y., and Singh, H.  (2015) Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8. Nature Immunology 16:1274-81

Olsson, A., Venkatasubramanian, M., Chaudhri, V., Aronow, B.J., Salomonis, N.*, Singh, H.*, Grimes, H.L.* (2016) Single-cell analysis of mixed-lineage states leading to a binary cell fate choice.  Nature 537:698-702. *co-senior authors; PMCID: PMC:5161694.

Chaudhri, V.K., Dienger-Stambaugh, K., Wu, Z., Shrestha, M., and Singh, H. Charting the cis-regulome of activated B cells by coupling structural and functional genomics. Nature Immunology 21:210-220 (2020).

Louis K, Bailly E, Macedo C, Lau L, Ramaswami B, Chang A, Chandran U, Landsittel D, Gu X, Chalasani G, Zeevi A, Randhawa P, Singh H*, Lefaucheur C*, Metes D*. T-bet+CD27+CD21- B cells poised for plasma cell differentiation during antibody-mediated rejection of kidney transplants. JCI Insight (2021) Jun 22;6(12):e148881. doi: 10.1172/jci.insight.148881. *co-senior authors

Chen D, Wang Y, Manakkat Vijay GK, Fu S, Nash CW, Xu D, He D, Salomonis N, Singh H*, Xu H*. Coupled analysis of transcriptome and BCR mutations reveals role of OXPHOS in affinity maturation. Nat Immunol. (2021) Jul;22(7):904-913. doi: 10.1038/s41590-021-00936-y. *co-senior authors. 10.1371/journal.pcbi.1008094. *co-senior authors

Xin Bing, Tyler Lovelace, Florentina Bunea, Marten Wegkamp, Sudhir Pai Kasturi, Harinder Singh*, Panayiotis V. Benos* and Jishnu Das*. Essential Regression: A generalizable framework for inferring causal latent factors from multi-omic datasets. Patterns (2022) https://doi.org/10.1016/j.patter.2022.100473 *co-senior authors

Full List of Publications