Projectdetails

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Regulation of aging and age-related disease by transcription factors, chromatin states, and the epigenome

Keywords:
epigenetics transcriptional regulation aging

Researchers:
dr. C.G. Riedel

Nature of the research:
Research in our lab studies the fundamental principles of ageing and lifespan regulation. We employ a wide array of genetic, biochemical, and molecular biology techniques, as well as high-throughput screening. Most of our work is conducted in the model system C. elegans.

Fields of study:
cell biology molecular biology genetics

Background / introduction
In these days of modern medicine, acute diseases are increasingly treatable, leaving ageing and age-related diseases as our major health and lifespan determinants. Fortunately, ageing is a plastic process, so that detailed understanding of its regulation should provide potent means to impair it and thus enhance our quality of life.
Ageing regulation is conferred by various signaling pathways that in response to dire conditions induce stress responses, which increase the organism’s durability and longevity and thus its chances of survival. At the core of this regulation stands the transcription factor DAF-16/FOXO, which integrates many lifespan extending stimuli, i.e. nutrient deprivation, various stresses, or cues of infertility to confer transcription of a wide range of stress resistance and longevity determining genes. Despite its importance, DAF-16/FOXO’s mechanisms of transcriptional regulation have remained largely elusive.
Research question / problem definition
Recently, we made important progress by identifying several cofactors to DAF-16/FOXO. By focusing on one of them, SWI/SNF, we could show that DAF-16/FOXO employs chromatin remodeling at its target promoters as a means to induce transcription. We are now excited to 1) explore this connection between ageing-regulation and chromatin changes to further depth, to broaden this study by understanding the role of the epigenome in aging regulation, and to 2) explore the remaining unstudied cofactors to DAF-16/FOXO.
Interested applicants are encouraged to contact us for an interview. During this visit the actual project will be defined, depending on the current state of our progress and the applicant’s interests. Nevertheless, the project will revolve around the aforementioned two aims.
Workplan
Any project will be carefully designed so that it contributes to top-level publications and can be accomplished in the anticipated timeframe of the student’s stay in the lab. The technical expertise of our lab is extensive and thus students will learn a wide array of techniques across the disciplines of biochemistry, molecular biology, and genetic screening approaches. These include protein purification, mass spectrometry, chromatin IP (ChIP-Seq), gene expression analysis (mRNA-Seq), high-throughput reverse-genetic screening by RNAi, stress-response and lifespan assays, microscopy, and many more.
For most of this work we use the model system C. Elegans. This organism is ideal for studies of aging, as it is technically well established, short-lived (allowing for lifespan as an easily measurable phenotype), and very responsive to alterations in its aging-regulatory pathways. At the same time its aging-regulatory mechanisms are highly conserved all the way to humans.
The student will be part of a highly motivated research team that provides excellent supervision and mentoring. In exchange we expect the student to be highly motivated and ambitious.
References
Riedel, C. G., Dowen, R. H., Lourenco, G. F., Kirienko, N. V, Heimbucher, T., West, J. a, … Ruvkun, G. (2013). DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nature Cell Biology, 15(5), 491–501.

Calnan, D. R., & Brunet, A. (2008). The FoxO code. Oncogene, 27(16), 2276–88.

Kenyon, C. (2005). The plasticity of aging: insights from long-lived mutants. Cell, 120(4), 449–60.

Curran, S. P., Wu, X., Riedel, C. G., & Ruvkun, G. (2009). A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. Nature, 459(7250), 1079–84.

Rizki, G., Iwata, T. N., Li, J., Riedel, C. G., Picard, C. L., Jan, M., … Lee, S. S. (2011). The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet., 7(9), e1002235.

Hayes, G. D., Riedel, C. G., & Ruvkun, G. (2011). The Caenorhabditis elegans SOMI-1 zinc finger protein and SWI/SNF promote regulation of development by the mir-84 microRNA. Genes & Development, 25(19), 2079–92.

Riedel, C. G., Katis, V. L., Katou, Y., Mori, S., Itoh, T., Helmhart, W., … Nasmyth, K. (2006). Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I. Nature, 441(7089), 53–61.
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