Our lab studies the mechanisms controlling gene expression in health and disease. Transcriptional regulation plays a fundamental role in development, homeostasis, and response to environmental cues. Indeed, gene dysregulation has been associated with multiple diseases such as immune disorders, developmental malformations, and cancer. After decades of research, however, many aspects gene 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. In addition, we have developed and implemented other experimental and computational tools to study gene regulation in a high-throughput manner. Our long-term goal is to answer central questions in gene 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? Through which mechanisms do non-coding mutations affect gene expression in cancer?
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: More than 90% of mutations found in cancer reside in non-coding regions of the genome. However, it is unclear how which of these are cancer drivers. Our goal is to predict non-coding driver mutations in cancer to provide insights into mechanisms involved in gene dysregulation. 3) Role of TF isoforms in cancer: Our goal is to determine how TF isoforms rewire gene regulatory networks in cancer. 4) Viral transcriptional regulators: Virus encode for transcriptional regulators that affect the expression of viral and host genes. Our goals is to characterize the functions of these regulators and determine their roles in disease.
- Carrasco Pro S, Hook H, Bray D, Moyer D, Yin M, Labadorf A, Tewhey R, *Siggers T, *Fuxman Bass J. Widespread perturbation of ETS factor binding sites in cancer. bioRxiv2022.05.09.491119. doi.org/10.1101/2022.08.10.503516. In press at Nature Communications. (*co-corresponding authors)
- Soto L, Li Z, Santoso CS, Berenson A, Ho I, Shen VX, Yuan S, Fuxman Bass JI. Compendium of human transcription factor effector domains. Molecular Cell. 2022 Feb 3;82(3):514-526. doi: 10.1016/j.molcel.2021.11.007
- Pedro KD, Agosto LM, Sewell JA, Eberenz KA, He X, *Fuxman Bass JI, *Henderson AJ. An unbiased functional screen identifies transcriptional networks that regulate HIV-1 and HIV-2. Proc Natl Acad Sci USA. 2021 Mar 16;118(11):e2012835118. doi: 10.1073/pnas.2012835118 (*co-corresponding and co-senior author).
- Santoso CS, Li Z, Lal S, Yuan S, Gan KA, Agosto LM, Liu X, Carrasco Pro S, Sewell JA, Henderson A, Atianand MK, Fuxman Bass JI. Comprehensive mapping of the human cytokine gene regulatory network. Nucleic Acids Research 2020 Dec 2;48(21):12055-12073. doi: 10.1093/nar/gkaa1055
- Liu X, Hong T, Parameswaran S, Ernst K, Marazzi I, *Weirauch MT, *Fuxman Bass JI. Human Virus Transcriptional Regulators. Cell. 2020 Jul 9;182(1):24-37. doi: 10.1016/j.cell.2020.06.023 (*co-corresponding and co-senior author
- Shrestha S, Sewell JA, Santoso CS, Forchielli E, Carrasco Pro S, Martinez M, Fuxman Bass JI. Discovering human transcription factor physical interactions with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays. Genome Research. 2019 Sep 29: 1533-1544; doi:10.1101/gr.248823.119″
- Carrasco Pro S, Dafonte Imedio A, Santoso CS, Gan KA, Sewell JA, Martinez M, Sereda R, Mehta S, Fuxman Bass JI. Global landscape of mouse and human cytokine transcriptional regulation. Nucleic Acids Res. 2018 Sep 3. doi: 10.1093/nar/gky787.
- 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. doi: 10.1016/j.cell.2015.03.003