Open position for a Postdoctoral fellow to investigate mechanisms of transcriptional regulation. Examples of potential research topics that build upon recent studies include: probing the roles and network of sequence-specific transcription factors in orchestrating genome-wide expression; studies on the specificity and mechanisms of transcription cofactors (e.g., Mediator, SAGA, TFIID); investigating the mechanisms and specificity of transcription enhancers and core promoters. The precise topic of the research project will be determined jointly with the candidate. Postdoctoral salary for 2023 is $65,484. Contact Steve to apply.
Mentoring of postdoctoral fellows is a high priority. The Hahn lab is committed to fostering an inclusive culture of diversity, within a highly creative environment and applications from people of all backgrounds is encouraged.
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Our laboratory studies a wide range of mechanisms that regulate the transcription of eukaryotic mRNAs. mRNA synthesis is regulated by many signaling pathways that control processes such as development, growth, and the response to environmental conditions such as stress. Even genes that are constitutively transcribed appear to be regulated by complex mechanisms that ensure mRNA synthesis rates are stable during different environmental conditions and cell cycle phases. Misregulation of transcription is a major cause of human disease and our work addresses the molecular basis for some of these defects. The lab uses a wide variety of experimental technologies to explore these topics such as molecular genetics, genomics, high throughput screening, computational biology, biochemistry, structural biology and biophysics. We use S. cerevisiae (budding yeast) as our experimental system because of the powerful mix of genomics, molecular genetics and biochemical methods that can readily be applied to this model organism. Because the transcription machinery and its regulatory factors are well-conserved throughout evolution, fundamental gene regulatory mechanisms in yeast are nearly always conserved in metazoans.
Mechanistic studies on eukaryotic transcription began over 50 years ago with the identification of the three forms of RNA Polymerase (Pol) and the discovery in the 1980’s of eukaryotic basal transcription factors. Since then, great progress has been made in identifying important principles of transcription and its regulation. These include: (i) the discovery of nearly all the gene-specific transcription factors (TFs), cofactor complexes, and components of the basal transcription machinery, (ii) recognition of the important roles that chromatin, chromatin modifications, and higher order chromosome architecture plays in gene regulation, and (iii) fundamental insights into the molecular mechanisms of gene-specific TFs, cofactors, and RNA polymerases. With this background, and the availability of important new technologies, this is an excellent time to tackle the next level of fundamental problems in gene regulation.
The work in our laboratory is focused on two problems central to eukaryotic transcriptional regulation: a) the function of gene-specific transcription factors, and b) the genome-wide specificity and mechanisms of transcription cofactors. These two problems are highly interrelated. For example, TFs, chromatin architecture, and promoter sequences play a critical role in determining cofactor requirements and the assembly pathway for the Pol II transcription machinery. Examples of some of our current projects are given below.
A major focus of the lab is to investigate the function of regulatory transcription factors that bind DNA in a sequence-specific fashion (TFs). Yeast contain ~ 150 TFs, about 10-fold less than mammalian cells, which make this a great model system to examine genome-wide functions and interactions between the complete set of TFs. In our initial studies, we have mapped the genome-wide binding locations for nearly all the TFs and found three distinct sets of genes that differ in the number and types of TFs that bind to upstream enhancer regions. To explore the function of TF binding, we have rapidly depleted individual factors and identified genes with altered transcription levels. These approaches have led to many surprising results. For example, we found that many TF binding sites do not obviously contribute to gene expression and that depletion of individual TFs often affects expression of genes that do not contain an obvious nearby binding site. These results have opened many new research directions. For example, we will be exploring why certain TF binding sites are functional vs nonfunctional, how individual TFs contribute to transcription and chromatin architecture, and how TF and cofactor activities are integrated to control genome-wide transcription.
Another research focus is investigating the mechanisms of transcription cofactors and how these functions are modulated by the sequence-specific TFs. For example, three conserved cofactors termed Mediator, SAGA and TFIID, integrate regulatory signals and that are links between regulatory transcription factors and the core transcription machinery. By combining genomics, molecular genetics, and biochemical approaches, we are investigating the gene-specificity of these cofactors and how they interact with regulatory transcription factors, the core transcription machinery, and each other to determine how they regulate transcription. For example, in a recent study we found that, in contrast to current models for Mediator function, the principal role of Mediator at many genes is not to function as a direct signaling target of transcription activators, but rather as an essential component of the transcription machinery at core promoters. In another example, we recently found that yeast contain three distinct types of protein-coding genes, each regulated by a specific set of coactivators. Finally, we are using Massively Parallel Reporter Assays (MRPAs) to investigate enhancer-promoter specificity, testing the function and cofactor specificity of nearly all yeast enhancers driving expression from three fundamental classes of yeast promoters.
Schofield, JA and S. Hahn (2022) Broad compatibility between yeast UAS elements and core promoters and identification of promoter elements that determine cofactor specificity. Biorxiv doi: https://doi.org/10.1101/2022.11.03.515066.
Warfield, L.*, Donczew, R.*, Mahendrawada, L., and S. Hahn (2022) Yeast Mediator facilitates transcription initiation at most promoters via a Tail-independent mechanism. Mol Cell, Nov 3;82(21):4033-4048.e7. doi: 10.1016/j.molcel.2022.09.016. Epub 2022 Oct 7.
Donczew, R and S. Hahn (2021). BET family members Bdf1/2 modulate global transcription initiation and elongation in Saccharomyces cerevisiae. Elife. 2021 Jun 17;10:e69619. doi: 10.7554/eLife.69619. Online ahead of print.PMID: 34137374
Tuttle, L.M., Pacheco, D., Warfield, L., Wilburn, D.L., Hahn, S., and Klevit, R.E. (2021). Mediator subunit Med15 dictates the conserved “fuzzy” binding mechanism of yeast transcription activators Gal4 and Gcn4. Nature Comm Nat Commun. Apr 13;12(1):2220. doi: 10.1038/s41467-021-22441-4..
Erijman, A., Kozlowski, L., Sohrabi-Jahromi, S., Fishburn, J., Warfield, L., Schreiber, J., Noble, W., Söding, J., and Hahn, S. (2020). A high-throughput screen for transcription activation domains reveals their sequence characteristics and permits reliable prediction by deep learning. Mol Cell May 12:S1097-2765(20)30262-8. doi: 10.1016/j.molcel.2020.04.020..
Donczew, R*., Warfield, L.*, Pacheco, D., Erijman, A., and Hahn, S. (2020). Two roles for the yeast transcription coactivator SAGA and a set of genes redundantly regulated by TFIID and SAGA. Elife 9, e50109. doi: 10.7554/eLife.50109. PMID: 31913117
Donczew, R., and Hahn, S. (2018). Mechanistic Differences in Transcription Initiation at TATA-Less and TATA-Containing Promoters. Molecular and Cellular Biology Dec 13;38(1). pii: e00448-17. doi: 10.1128/MCB.00448-17. PMID: 29038161.
Pacheco, D*., Warfield, L*., Brajcich, M., Robbins, H., Luo, J., Ranish, J., and Hahn, S. (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 Apr 30;38(10). pii: e00038-18. doi: 10.1128/MCB.00038-18. PMID: 29507182
Tuttle, L.M., Pacheco, D., Warfield, L., Luo, J., Ranish, J., Hahn, S., and Klevit, R.E. (2018). Gcn4-Mediator Specificity Is Mediated by a Large and Dynamic Fuzzy Protein-Protein Complex. Cell Rep 22, 3251–3264.
Hahn S. (2018). Phase Separation, Protein Disorder, and Enhancer Function. Cell 175:1723-1725. doi: 10.1016/j.cell.2018.11.034.