Our lab studies the mechanisms controlling the expression of immune genes. Transcriptional regulation plays a fundamental role in proper immune development and homeostasis as well as in mounting immune responses against pathogens. Indeed, mutations in the regulatory regions of immune genes such as cytokines, receptors and signaling molecules have been associated with multiple pathologies including autoimmune diseases, cancer and susceptibility to infections. After decades of research, however, many aspects of immune transcriptional regulation are still not well understood, as most studies have focused on only a few dozen of the ~1,500 human transcription factors (TFs) leaving a large portion of the gene regulatory network unexplored. This bias towards a limited number of TFs is both historical and methodological, as TFs with available reagents are more highly studied and current methods such as chromatin immunoprecipitation (ChIP) test one TF at a time.
We have recently developed an enhanced yeast one-hybrid (eY1H) platform that can interrogate for the binding of 1,086 human TFs (out of ~1,500) to different regulatory regions. Our main goal is to delineate an unbiased immune gene regulatory network by comprehensively identifying the TFs that bind to the regulatory regions of different immune genes and to determine which TF-DNA interactions are affected by disease-associated mutations in non-coding regions. To achieve this goal we use an interdisciplinary approach that merges high-throughput screening of TF-DNA interactions using eY1H assays, functional genomics, bioinformatics and cell biology. Our long-term goal is to answer central questions in immune regulation such as: through which mechanisms are immune genes regulated during inflammatory processes? How can we modulate the regulatory network in immune cells to more effectively respond to infectious diseases and pathological conditions? How do non-coding mutations impact immune gene expression leading to disease?
Current projects in the lab include: 1) Cytokine regulation: Cytokines are key cell-to-cell communication proteins that regulate immune development and responses. Our goal is to delineate a comprehensive network involved in the regulation of cytokine genes that will not only help us understand how immune responses are orchestrated, but may also lead to the development of therapeutics to modulate cytokine expression in disease. 2) Disease mutations: About 90% of mutations associated with disease reside in non-coding regions of the genome, most in transcriptional control regions potentially affecting TF binding sites. However, the identity of the TFs with altered binding remains undetermined for the majority of these mutations. Our goal is to identify these TF binding changes for different mutations associated with immune disorders to provide insights into disease mechanisms.
- Fuxman Bass JI, Sahni N, Shrestha S, Garcia-Gonzalez A, Mori A, Bhat N, Yi S, Hill DE, Vidal M, Walhout AJ. Human Gene-Centered Transcription Factor Networks for Enhancers and Disease Variants. Cell. 2015 Apr 23;161(3): 661-73.
- *Sahni N, *Yi S, *Taipale M, *Fuxman Bass JI, *Coulombe-Huntington J, Yang F, Peng J, Weile J, Karras GI, Wang Y, Kovács IA, Kamburov A, Krykbaeva I, Lam MH, Tucker G, Khurana V, Sharma A, Liu YY, Yachie N, Zhong Q, Shen Y, Palagi A, San-Miguel A, Fan C, Balcha D, Dricot A, Jordan DM, Walsh JM, Shah AA, Yang X, Stoyanova AK, Leighton A, Calderwood MA, Jacob Y, Cusick ME, Salehi-Ashtiani K, Whitesell LJ, Sunyaev S, Berger B, Barabási AL, Charloteaux B, Hill DE, Hao T, Roth FP, Xia Y, Walhout AJ, Lindquist S, Vidal M. Widespread Perturbation of Disease-Specific Macromolecular Interactions in Human Genetic Disorders. Cell. 2015 Apr 23;161(3): 647-60. (*co-first author).
- Fuxman Bass JI, Diallo A, Nelson J, Soto JM, Myers CL, Walhout AJ. Using networks to measure similarity between genes: association index selection. Nature Methods. 2013 Dec. 10(12): 1169-76.
- Fuxman Bass JI, Tamburino AM, Mori A, Beittel N, Weirauch MT, Reece-Hoyes JS, Walhout AJ. Transcription factor binding to Caenorhabditis elegans first introns reveals lack of redundancy with gene promoters. Nucleic Acids Res. 2013 Sep 24. 153-62.
- Ritter AD, Shen Y, Fuxman Bass J, Jeyaraj S, Deplancke B, Mukhopadhyay A, Xu J, Driscoll M, Tissenbaum HA, Walhout AJ. Complex expression dynamics and robustness in C. elegans insulin networks. Genome Research. 2013 Jun;23(6): 954-65.
- Fuxman Bass J, Russo D, Gabelloni M, Geffner J, Giordano M, Catalano M, Zorreguieta A, Trevani A. Extracellular DNA: A Major Proinflammatory Component of P. aeruginosa Biofilms. J Immunol. 2010 Jun 1;184(11): 6386-95.
- Fuxman Bass J, Alvarez M, Gabelloni M, Geffner J, Vermeulen M, Amaral M, Trevani A. GM-CSF enhances a CpG-independent pathway of neutrophil activation triggered by bacterial DNA. Mol Immunol. 2008 Nov;46(1): 37-44.
- Fuxman Bass J, Gabelloni M, Alvarez M, Vermeulen M, Russo D, Zorreguieta A, Geffner J, Trevani A. Characterization of bacterial DNA binding to human neutrophil surface. Lab Invest. 2008 Sep;88(9): 926-37.