Chromatin control of environmental stress response
Research Summary
Cells respond to environmental stress by mounting an adaptive stress response in order to survive stressful conditions. Transcriptional control is a major regulatory layer that determines the strength, the duration and persistence of cellular stress response. Transcription factors, chromatin modifications and non-coding RNA influence the transcriptional response to environmental stress. The molecular mechanisms by which chromatin exerts control over stress response is the main focus of the Unit programme.
Research Objectives
We aim to address the following questions:
- Which cellular pathways sense environmental stress/ toxins and signal to the genome?
- How does chromatin interpret the information about cellular health and toxic exposure determining the transcriptional response to stress?
- How does the transcriptional response adapt cellular phenotypes to survive the stress?
We study these three questions in the context of cellular exposure to environmental stress as well as small-molecule therapeutics in collaboration with pharmaceutical companies. Our approaches include genomics, single-cell transcriptomics, proteomics, chromatin biochemistry as well as genome-wide screening to identify novel components of stress-response pathways. Discovery-driven global approaches in mammalian cells are further validated by in vitro reconstitution experiments and mouse genetic models. We aim to gain novel insights and mechanistic understanding of transcriptional response to stress and toxins.
Key Publications
Leone S, Srivastava A, Herrero-Ruiz A, Hummel B, Tittel L, Campalastri R, Aprile-Garcia F, Tan JH, Rawat P, Andersson P, Willis WE, Sawarkar R. HSP70 binds to specific non-coding RNA and regulates human RNA polymerase III. Mol Cell. 84(4), 687-701, (2024).
Rawat P, Boehning M, Hummel B, Aprile-Garcia F, Pandit AS, Eisenhardt N, Khavaran A, Niskanen E, Vos SM, Palvimo JJ, Pichler A, Cramer P, Sawarkar R. (2021) Stress-induced nuclear condensation of NELF drives transcriptional downregulation. Mol Cell. doi: 10.1016/j.molcel.2021.01.016.
Antonova A, Hummel B, Khavaran A, Redhaber D, Aprile Garcia F, Rawat P, Gundel K, Schneck M, Hansen E, Mitschke J, Mittler G, Miething C and Sawarkar R (2019) Heat-shock protein 90 controls the expression of cell-cycle genes by stabilizing metazoan-specific Host-Cell Factor HCFC1. Cell Reports. 29(6):1645-1659.e9.
Aprile-Garcia F, Tomar P, Hummel B, Khavaran A, Sawarkar R. ‘Nascent-protein ubiquitination is required for heat shock-induced gene downregulation in human cells.’ Nat Struct Mol Biol. 2019 Feb;26(2):137-146. doi: 10.1038/s41594-018-0182-x. Epub 2019 Feb 4. PMID: 30723328
Irmak D, Fatima A, Gutiérrez-Garcia R, Rinschen MM, Wagle P, Altmüller J, Arrigoni L, Hummel B, Klein C, Frese CK, Sawarkar R, Rada-Iglesias A, Vilchez D. ‘Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations.’ Hum Mol Genet. 2018 Dec 1;27(23):4117-4134. doi: 10.1093/hmg/ddy304. PMID:30452683
Vincenz-Donnelly L, Holthusen H, Körner R, Hansen EC, Presto J, Johansson J, Sawarkar R, Hartl FU, Hipp MS. ‘High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins.’ EMBO J. 2018 Feb 1;37(3):337-350. doi: 10.15252/embj.201695841. Epub 2017 Dec 15. PMID:29247078
Full Publication List
Ritwick Sawarkar
MRC Toxicology Unit, Gleeson Building