A major aim of the Integrative Immunobiology Unit is to decipher gene expression programs that direct cell fates in the hematopoietic and immune system. We seek knowledge that will provide insights for understanding immunodeficiencies, autoimmunities and effective immune responses. For a tractable model system to prototype our approaches, we are taking advantage of CD4+ T helper cell differentiation since many research tools are available for this system and much is already known about its core transcriptional program and signaling pathways. However, relatively little is known about post-transcriptional control of gene expression and the roles of non-coding RNAs in this context. The focus of this project is a class of endogenous small untranslated RNAs called microRNAs (miRNAs) that partner with Argonaute (Ago) proteins to form effector RNA-induced silencing complexes (RISCs) that recognize cognate mRNA targets and reduce their stability. It became evident that miRNAs are required for B and T lymphocyte differentiation when miRNA biogenesis was blocked by conditional ablation of the processing enzyme Dicer in a genetically engineered mouse model. Previously, we successfully combined mouse genetics and genomics to systematically determine the impact of miRNAs on the transcriptome. We will continue with this approach to integrate miRNAs into maps of regulatory networks that orchestrate gene expression in lymphocytes. To accomplish our goals we are establishing state-of-the-art genomic methods enabled by massively parallel sequencing.

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Kanellopoulou, Chrysi; Muljo, Stefan A (2018) Posttranscriptional (Re)programming of Cell Fate: Examples in Stem Cells, Progenitor, and Differentiated Cells. Front Immunol 9:715
Kanellopoulou, Chrysi; Muljo, Stefan A (2016) Fine-Tuning Th17 Cells: To Be or Not To Be Pathogenic? Immunity 44:1241-3
Bhairavabhotla, Ravikiran; Kim, Yong C; Glass, Deborah D et al. (2016) Transcriptome profiling of human FoxP3+ regulatory T cells. Hum Immunol 77:201-13
Witte, Steven; Bradley, Allan; Enright, Anton J et al. (2015) High-density P300 enhancers control cell state transitions. BMC Genomics 16:903
Mayer, Bryan T; Srinivasan, Sujatha; Fiedler, Tina L et al. (2015) Rapid and Profound Shifts in the Vaginal Microbiota Following Antibiotic Treatment for Bacterial Vaginosis. J Infect Dis 212:793-802
Luck, Marisa E; Muljo, Stefan A; Collins, Colm B (2015) Prospects for Therapeutic Targeting of MicroRNAs in Human Immunological Diseases. J Immunol 194:5047-52
Schmid, Michael; Smith, Jacqueline; Burt, David W et al. (2015) Third Report on Chicken Genes and Chromosomes 2015. Cytogenet Genome Res 145:78-179
Kanellopoulou, Chryssa; Gilpatrick, Timothy; Kilaru, Gokhul et al. (2015) Reprogramming of Polycomb-Mediated Gene Silencing in Embryonic Stem Cells by the miR-290 Family and the Methyltransferase Ash1l. Stem Cell Reports 5:971-978
Witte, Steven; Muljo, Stefan A (2014) Integrating non-coding RNAs in JAK-STAT regulatory networks. JAKSTAT 3:e28055
Escobar, Thelma M; Kanellopoulou, Chrysi; Kugler, David G et al. (2014) miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Immunity 40:865-79

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