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Ranish Lab Overview

“Deciphering the topology of molecular interaction networks is critical to understanding what goes wrong when cells become diseased.”

–Jeff Ranish, PhD, Professor
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Proteins play central roles in essentially all cellular processes by interacting with one another and with other molecules in complexes and networks to control information flow through biological systems. Elucidating the composition and architecture of these macromolecular complexes and interaction networks is a fundamental step towards understanding how information flows through biological systems in both health and disease. The Ranish group develops and applies mass spectrometry-based proteomics technologies to decipher the composition and architecture of macromolecular complexes and networks with a focus on complexes/networks involved in gene regulation.This information is critical for understanding the molecular interactions that control cellular processes, which in turn, is essential in using systems biology to transform medicine, energy production and environmental protection.

Research Overview

A particular focus of the research done by Jeff Ranish and his colleagues has been the complexes that control expression of protein coding genes at the level of transcription. These complexes can be very large and their composition often changes in response to cellular and environmental conditions.  For example, in macrophages, the liver X receptor (LXR) transcription factors regulate expression of target genes in response to different stimuli by interacting with co-activator or co-repressor proteins. To understand how LXR protein complexes control expression of cholesterol efflux genes, the Ranish group developed a promoter enrichment-quantitative mass spectrometry approach to characterize the composition of complexes that assemble at the regulatory elements of these genes under different conditions. This led to the discovery of a number of LXR interacting proteins that are required for proper control of cholesterol efflux genes in response to lipid and inflammatory signals. Because dysregulation of cholesterol efflux can lead to intracellular cholesterol accumulation and the formation of atherosclerosis-promoting foam cells, these proteins and their interactions may represent targets for the development of therapeutics for the treatment of atherosclerosis.

To decipher the structural basis for protein complex function, the group has developed chemical crosslinking-mass spectrometry (CLMS) technologies, including novel crosslinking reagents, methodologies, and computational programs that can provide information about subunit proximity within protein complexes. Often computational approaches are used to integrate the CLMS information with other sources of structural data to obtain models with higher resolution. These models can then be used to develop strategies to control the activity of the complexes in desired ways. The group has used this approach to determine the architecture of several large transcriptional regulatory complexes including the general transcription factor TFIIH, the TFIID co-activator complex, and the SWI-SNF chromatin remodeling complex.

CLMS also holds promise for allowing routine studies of protein-protein interaction networks and their dynamics on a large scale. The Ranish lab is developing crosslinking reagents, methodologies, and computational approaches to allow routine and confident mapping of global and dynamic PPIs.

The Ranish lab also is developing mass spectrometry-based approaches to systematically detect and quantify specific proteins such as transcription factors during dynamic processes such as cell differentiation. Changes in transcription factor abundance and stoichiometry drive cell state changes, in part by affecting molecular interactions. However, our understanding of these complex relationships is limited by the paucity of nuclear protein concentration information. To address this issue, the group developed a targeted mass spectrometry approach to quantify the absolute abundances of large numbers of TFs and cofactors across multiple sequential time points during human erythropoiesis.  In doing so, they defined the protein concentration (copies/nucleus) for master regulators of hematopoiesis/erythropoiesis, as well as coregulators of transcription, thereby providing a quantitative scale for human TFs in the nucleus (http://apps.systemsbiology.net/app/Transcription_Factor_Protein_RNA_Erythropoiesis). In addition, comparison of protein and mRNA expression patterns suggests that many TFs are regulated by post-transcriptional mechanisms. By integrating these absolute protein abundances with mRNA measurements they generated a dynamic gene regulatory network of erythroid commitment (http://grns.biotapestry.org/HumanErythropoiesisGRN/). These data provide unique and important information for understanding the transcriptional regulatory programs controlling erythropoiesis, as well as general mechanisms that may regulate cell fate decisions in different systems.

By providing an in-depth understanding of how genes are turned on and off, the research will reveal information that is key to determining how cells function in health and disease. Understanding these processes will make it possible to reprogram the behavior of cells when the dysregulation of gene expression results in disease.

Publications

Wenderski, Wendy, Lu Wang, Andrey Krokhotin, Jessica J. Walsh, Hongjie Li, Hirotaka Shoji, Shereen Ghosh, et al. 2020. “Loss of the Neural-Specific BAF Subunit ACTL6B Relieves Repression of Early Response Genes and Causes Recessive Autism.” Proceedings of the National Academy of Sciences of the United States of America, April. https://doi.org/10.1073/pnas.1908238117. Cite Download
Kim, Mun Kyoung, An Tranvo, Ann Marie Hurlburt, Neha Verma, Phuc Phan, Jie Luo, Jeff Ranish, and William E. Stumph. 2020. “Assembly of SNAPc, Bdp1, and TBP on the U6 SnRNA Gene Promoter in Drosophila Melanogaster.” Molecular and Cellular Biology, April. https://doi.org/10.1128/MCB.00641-19. Cite
Patel, Avinash B., Camille M. Moore, Basil J. Greber, Jie Luo, Stefan A. Zukin, Jeff Ranish, and Eva Nogales. 2019. “Architecture of the Chromatin Remodeler RSC and Insights into Its Nucleosome Engagement.” ELife 8. https://doi.org/10.7554/eLife.54449. Cite Download
Hada, Arjan, Swetansu K. Hota, Jie Luo, Yuan-Chi Lin, Seyit Kale, Alexey K. Shaytan, Saurabh K. Bhardwaj, et al. 2019. “Histone Octamer Structure Is Altered Early in ISW2 ATP-Dependent Nucleosome Remodeling.” Cell Reports 28 (1): 282-294.e6. https://doi.org/10.1016/j.celrep.2019.05.106. Cite Download
Luo, Jie, Jacob Bassett, and Jeff Ranish. 2019. “Identification of Cross-Linked Peptides Using Isotopomeric Cross-Linkers.” Journal of the American Society for Mass Spectrometry. https://doi.org/10.1007/s13361-019-02253-z. Cite
Palii, Carmen G., Qian Cheng, Mark A. Gillespie, Paul Shannon, Michalina Mazurczyk, Giorgio Napolitani, Nathan D. Price, et al. 2019. “Single-Cell Proteomics Reveal That Quantitative Changes in Co-Expressed Lineage-Specific Transcription Factors Determine Cell Fate.” Cell Stem Cell 24 (5): 812-820.e5. https://doi.org/10.1016/j.stem.2019.02.006. Cite
Patel, Avinash B., Robert K. Louder, Basil J. Greber, Sebastian Grünberg, Jie Luo, Jie Fang, Yutong Liu, Jeff Ranish, Steve Hahn, and Eva Nogales. 2018. “Structure of Human TFIID and Mechanism of TBP Loading onto Promoter DNA.” Science (New York, N.Y.) 362 (6421). https://doi.org/10.1126/science.aau8872. Cite
Kolesnikova, Olga, Adam Ben-Shem, Jie Luo, Jeff Ranish, Patrick Schultz, and Gabor Papai. 2018. “Molecular Structure of Promoter-Bound Yeast TFIID.” Nature Communications 9 (1): 4666. https://doi.org/10.1038/s41467-018-07096-y. Cite Download
Mashtalir, Nazar, Andrew R. D’Avino, Brittany C. Michel, Jie Luo, Joshua Pan, Jordan E. Otto, Hayley J. Zullow, et al. 2018. “Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes.” Cell 175 (5): 1272-1288.e20. https://doi.org/10.1016/j.cell.2018.09.032. Cite
Tuttle, Lisa M., Derek Pacheco, Linda Warfield, Jie Luo, Jeff Ranish, Steven Hahn, and Rachel E. Klevit. 2018. “Gcn4-Mediator Specificity Is Mediated by a Large and Dynamic Fuzzy Protein-Protein Complex.” Cell Reports 22 (12): 3251–64. https://doi.org/10.1016/j.celrep.2018.02.097. Cite
Pacheco, Derek, Linda Warfield, Michelle Brajcich, Hannah Robbins, Jie Luo, Jeff Ranish, and Steven Hahn. 2018. “Transcription Activation Domains of the Yeast Factors Met4 and Ino2: Tandem Activation Domains with Properties Similar to the Yeast Gcn4 Activator.” Molecular and Cellular Biology. https://doi.org/10.1128/MCB.00038-18. Cite
Turkarslan, Serdar, Arjun V. Raman, Anne W. Thompson, Christina E. Arens, Mark A. Gillespie, Frederick von Netzer, Kristina L. Hillesland, et al. 2017. “Mechanism for Microbial Population Collapse in a Fluctuating Resource Environment.” Molecular Systems Biology 13 (3): 919. Cite
Sen, Payel, Jie Luo, Arjan Hada, Solomon G. Hailu, Mekonnen Lemma Dechassa, Jim Persinger, Sandipan Brahma, Somnath Paul, Jeff Ranish, and Blaine Bartholomew. 2017. “Loss of Snf5 Induces Formation of an Aberrant SWI/SNF Complex.” Cell Reports 18 (9): 2135–47. https://doi.org/10.1016/j.celrep.2017.02.017. Cite
Nakayama, Robert T., John L. Pulice, Alfredo M. Valencia, Matthew J. McBride, Zachary M. McKenzie, Mark A. Gillespie, Wai Lim Ku, et al. 2017. “SMARCB1 Is Required for Widespread BAF Complex-Mediated Activation of Enhancers and Bivalent Promoters.” Nature Genetics. https://doi.org/10.1038/ng.3958. Cite
McDermott, Suzanne M., Jie Luo, Jason Carnes, Jeff A. Ranish, and Kenneth Stuart. 2016. “The Architecture of Trypanosoma Brucei Editosomes.” Proceedings of the National Academy of Sciences of the United States of America 113 (42): E6476–85. https://doi.org/10.1073/pnas.1610177113. Cite
Warfield, Linda, Jie Luo, Jeffrey Ranish, and Steven Hahn. 2016. “Function of Conserved Topological Regions within the S. Cerevisiae Basal Transcription Factor TFIIH.” Molecular and Cellular Biology. https://doi.org/10.1128/MCB.00182-16. Cite
Luo, J., P. Cimermancic, S. Viswanath, C. C. Ebmeier, B. Kim, M. Dehecq, V. Raman, et al. 2015. “Architecture of the Human and Yeast General Transcription and DNA Repair Factor TFIIH.” Molecular Cell 59 (September): 794–806. https://doi.org/10.1016/j.molcel.2015.07.016. Cite
Gillespie, Mark A., Elizabeth S. Gold, Stephen A. Ramsey, Irina Podolsky, Alan Aderem, and Jeffrey A. Ranish. 2015. “An LXR-NCOA5 Gene Regulatory Complex Directs Inflammatory Crosstalk-Dependent Repression of Macrophage Cholesterol Efflux.” The EMBO Journal 34 (9): 1244–58. https://doi.org/10.15252/embj.201489819. Cite
Kapoor, Prabodh, Yunhe Bao, Jing Xiao, Jie Luo, Jianfeng Shen, Jim Persinger, Guang Peng, Jeff Ranish, Blaine Bartholomew, and Xuetong Shen. 2015. “Regulation of Mec1 Kinase Activity by the SWI/SNF Chromatin Remodeling Complex.” Genes & Development 29 (6): 591–602. https://doi.org/10.1101/gad.257626.114. Cite
Wang, Lanfeng, Oliver Limbo, Jia Fei, Lu Chen, Bong Kim, Jie Luo, Jenny Chong, et al. 2014. “Regulation of the Rhp26ERCC6/CSB Chromatin Remodeler by a Novel Conserved Leucine Latch Motif.” Proceedings of the National Academy of Sciences of the United States of America 111 (52): 18566–71. https://doi.org/10.1073/pnas.1420227112. Cite
Han, Yan, Jie Luo, Jeffrey Ranish, and Steven Hahn. 2014. “Architecture of the Saccharomyces Cerevisiae SAGA Transcription Coactivator Complex.” The EMBO Journal 33 (21): 2534–46. https://doi.org/10.15252/embj.201488638. Cite
Taylor, Andrew F., Susan K. Amundsen, Miklos Guttman, Kelly K. Lee, Jie Luo, Jeffrey Ranish, and Gerald R. Smith. 2014. “Control of RecBCD Enzyme Activity by DNA Binding- and Chi Hotspot-Dependent Conformational Changes.” Journal of Molecular Biology 426 (21): 3479–99. https://doi.org/10.1016/j.jmb.2014.07.017. Cite
Knutson, Bruce A., Jie Luo, Jeffrey Ranish, and Steven Hahn. 2014. “Architecture of the Saccharomyces Cerevisiae RNA Polymerase I Core Factor Complex.” Nature Structural & Molecular Biology 21 (9): 810–16. https://doi.org/10.1038/nsmb.2873. Cite
Kadoch, C., D. C. Hargreaves, C. Hodges, L. Elias, L. Ho, J. Ranish, and G. R. Crabtree. 2013. “Proteomic and Bioinformatic Analysis of Mammalian SWI/SNF Complexes Identifies Extensive Roles in Human Malignancy.” Nat Genet, May. Cite
Sun, B., A. G. Utleg, Z. Hu, S. Qin, A. Keller, C. Lorang, L. Gray, et al. 2013. “Glycocapture-Assisted Global Quantitative Proteomics (GagQP) Reveals Multiorgan Responses in Serum Toxicoproteome.” Journal of Proteome Research, March. Cite
Mirzaei, H., T. A. Knijnenburg, B. Kim, M. Robinson, P. Picotti, G. W. Carter, S. Li, et al. 2013. “Systematic Measurement of Transcription Factor-DNA Interactions by Targeted Mass Spectrometry Identifies Candidate Gene Regulatory Proteins.” Proceedings of the National Academy of Sciences of the United States of America 110 (9): 3645–50. Cite
Akiyoshi, B., C. R. Nelson, N. Duggan, S. Ceto, J. Ranish, and S. Biggins. 2013. “The Mub1/Ubr2 Ubiquitin Ligase Complex Regulates the Conserved Dsn1 Kinetochore Protein.” PLoS Genet 9 (2): e1003216. Cite
Kloet, S. L., J. L. Whiting, P. Gafken, J. Ranish, and E. H. Wang. 2012. “Phosphorylation-Dependent Regulation of Cyclin D1 and Cyclin A Gene Transcription by TFIID Subunits TAF1 and TAF7.” Molecular and Cellular Biology 32 (16): 3358–69. Cite
London, Nitobe, Steven Ceto, J. Ranish, and Sue Biggins. 2012. “Phosphoregulation of Spc105 by Mps1 and PP1 Regulates Bub1 Localization to Kinetochores.” Curr Biol 22 (May): 900–906. https://doi.org/10.1016/j.cub.2012.03.052. Cite
Luo, J., J. Fishburn, S. Hahn, and J. Ranish. 2012. “An Integrated Chemical Cross-Linking and Mass Spectrometry Approach to Study Protein Complex Architecture and Function.” Molecular & Cellular Proteomics : MCP 11 (2): M111 008318. Cite
Yan, W., J. Luo, M. Robinson, J. Eng, R. Aebersold, and J. Ranish. 2011. “Index-Ion Triggered MS2 Ion Quantification: A Novel Proteomics Approach for Reproducible Detection and Quantification of Targeted Proteins in Complex Mixtures.” Mol Cell Proteomics 10 (3): M110 005611. Cite
Heldring, N., G. D. Isaacs, A. G. Diehl, M. Sun, E. Cheung, J. Ranish, and W. L. Kraus. 2011. “Multiple Sequence-Specific DNA-Binding Proteins Mediate Estrogen Receptor Signaling through a Tethering Pathway.” Mol Endocrinol, February. Cite
Himeda, C. L., J. Ranish, R. C. Pearson, M. Crossley, and S. D. Hauschka. 2010. “KLF3 Regulates Muscle-Specific Gene Expression and Synergizes with Serum Response Factor on KLF Binding Sites.” Mol Cell Biol 30 (14): 3430–43. Cite
Gillespie, M. A., F. Le Grand, A. Scime, S. Kuang, J. von Maltzahn, V. Seale, A. Cuenda, J. Ranish, and M. A. Rudnicki. 2009. “P38-Gamma-Dependent Gene Silencing Restricts Entry into the Myogenic Differentiation Program.” J Cell Biol 187 (7): 991–1005. Cite
Akiyoshi, B., C. R. Nelson, J. Ranish, and S. Biggins. 2009. “Quantitative Proteomic Analysis of Purified Yeast Kinetochores Identifies a PP1 Regulatory Subunit.” Genes Dev 23 (24): 2887–99. Cite
Akiyoshi, B., C. R. Nelson, J. Ranish, and S. Biggins. 2009. “Analysis of Ipl1-Mediated Phosphorylation of the Ndc80 Kinetochore Protein in Saccharomyces Cerevisiae.” Genetics 183 (4): 1591–95. Cite
Chaturvedi, C. P., A. M. Hosey, C. Palii, C. Perez-Iratxeta, Y. Nakatani, J. Ranish, F. J. Dilworth, and M. Brand. 2009. “Dual Role for the Methyltransferase G9a in the Maintenance of Beta-Globin Gene Transcription in Adult Erythroid Cells.” Proc Natl Acad Sci U S A 106 (43): 18303–8. Cite
Liu, Y., L. Warfield, C. Zhang, J. Luo, J. Allen, W. H. Lang, J. Ranish, K. M. Shokat, and S. Hahn. 2009. “Phosphorylation of the Transcription Elongation Factor Spt5 by Yeast Bur1 Kinase Stimulates Recruitment of the PAF Complex.” Mol Cell Biol 29 (17): 4852–63. Cite
Miles, G. P., M. A. Samuel, J. Ranish, S. M. Donohoe, G. M. Sperrazzo, and B. E. Ellis. 2009. “Quantitative Proteomics Identifies Oxidant-Induced, AtMPK6-Dependent Changes in Arabidopsis Thaliana Protein Profiles.” Plant Signal Behav 4 (6): 497–505. Cite
Ho, L., J. L. Ronan, J. Wu, B. T. Staahl, L. Chen, A. Kuo, J. Lessard, A. I. Nesvizhskii, J. Ranish, and G. R. Crabtree. 2009. “An Embryonic Stem Cell Chromatin Remodeling Complex, EsBAF, Is Essential for Embryonic Stem Cell Self-Renewal and Pluripotency.” Proc Natl Acad Sci U S A 106 (13): 5181–86. Cite
Kao, S. C., H. Wu, J. Xie, C. P. Chang, J. Ranish, I. A. Graef, and G. R. Crabtree. 2009. “Calcineurin/NFAT Signaling Is Required for Neuregulin-Regulated Schwann Cell Differentiation.” Science 323 (5914): 651–54. Cite
Picotti, P., H. Lam, D. Campbell, E. W. Deutsch, H. Mirzaei, J. Ranish, B. Domon, and R. Aebersold. 2008. “A Database of Mass Spectrometric Assays for the Yeast Proteome.” Nat Methods 5 (11): 913–14. Cite
Himeda, C. L., J. Ranish, and S. D. Hauschka. 2008. “Quantitative Proteomic Identification of MAZ as a Transcriptional Regulator of Muscle-Specific Genes in Skeletal and Cardiac Myocytes.” Mol Cell Biol 28 (20): 6521–35. Cite
Rubio, E. D., D. J. Reiss, P. L. Welcsh, C. M. Disteche, G. N. Filippova, N. S. Baliga, R. Aebersold, J. Ranish, and A. Krumm. 2008. “CTCF Physically Links Cohesin to Chromatin.” Proc Natl Acad Sci U S A 105 (24): 8309–14. Cite
Qi, Y., J. Ranish, X. Zhu, A. Krones, J. Zhang, R. Aebersold, D. W. Rose, M. G. Rosenfeld, and C. Carriere. 2008. “Atbf1 Is Required for the Pit1 Gene Early Activation.” Proc Natl Acad Sci U S A 105 (7): 2481–86. Cite
Kim, B., A. I. Nesvizhskii, P. G. Rani, S. Hahn, R. Aebersold, and J. Ranish. 2007. “The Transcription Elongation Factor TFIIS Is a Component of RNA Polymerase II Preinitiation Complexes.” Proc Natl Acad Sci U S A 104 (41): 16068–73. Cite
Demers, C., C. P. Chaturvedi, J. Ranish, G. Juban, P. Lai, F. Morle, R. Aebersold, F. J. Dilworth, M. Groudine, and M. Brand. 2007. “Activator-Mediated Recruitment of the MLL2 Methyltransferase Complex to the Beta-Globin Locus.” Mol Cell 27 (4): 573–84. Cite
Choi, J., B. Kim, K. Heo, K. Kim, H. Kim, Y. Zhan, J. Ranish, and W. An. 2007. “Purification and Characterization of Cellular Proteins Associated with Histone H4 Tails.” J Biol Chem 282 (29): 21024–31. Cite
Lessard, J., J. I. Wu, J. Ranish, M. Wan, M. M. Winslow, B. T. Staahl, H. Wu, R. Aebersold, I. A. Graef, and G. R. Crabtree. 2007. “An Essential Switch in Subunit Composition of a Chromatin Remodeling Complex during Neural Development.” Neuron 55 (2): 201–15. Cite
Heo, K., B. Kim, K. Kim, J. Choi, H. Kim, Y. Zhan, J. Ranish, and W. An. 2007. “Isolation and Characterization of Proteins Associated with Histone H3 Tails in Vivo.” J Biol Chem 282 (21): 15476–83. Cite