Our Focus
Gene expression is tightly regulated to ensure that genes are transcribed in the right cell at the right time. Yet, even genetically-identical cells in the same differentiation state and in the same environment exhibit considerable variability and fluctuations in the transcriptional process. This stochastic gene expression variation can influence important cell fate decisions and can also contribute to heterogeneity in tumours. A major source of stochastic gene expression heterogeneity is transcriptional bursting, where genes are transcribed during short periods of high gene activity interspersed by periods of inactivity. The origin and regulators of bursting remain largely unknown. Our lab aims to understand the regulatory mechanisms of transcriptional bursting in single cells. We use a range of single-molecule imaging techniques to directly observe the stochastic behaviour of regulatory factors and the process of transcription, as these dynamically occur inside living yeast and mammalian cells. We reveal how bursting is regulated by transcription factor binding dynamics, transcription factor clustering, enhancer-promoter interactions, chromatin, and DNA supercoiling. In addition, we are starting to apply our live-cell imaging approaches to study the function of stochastic heterogeneity in for example cancer plasticity.
About Tineke Lenstra
Tineke Lenstra
My Research
Tineke Lenstra received her Bachelor's' and Master's' degree in biomedical sciences from Utrecht University (cum laude). In 2008, she joined the laboratory of Frank Holstege at University Medical Centre Utrecht, where she used genome-wide expression analysis to study transcription regulatory complexes. She was awarded a cum laude PhD in 2012. As a postdoc in laboratory of Dan Larson at the National Cancer Institute in Bethesda, USA, she used cutting-edge single-molecule techniques to study transcription dynamics in single cells. In 2016, she established an independent group at the Netherlands Cancer Institute (NKI) in Amsterdam, where her lab applies and further develops single-molecule imaging techniques in living cells to understand the regulatory mechanisms and dynamics of stochastic transcription in eukaryotic cells.
For her work, Tineke has received a number of awards, including the KNAW early career award, the NVBMB prize, the Fellows Award for Research Excellence, the NCI Director's Innovation Award and the “Cancer Genomics and Developmental Biology” PhD Student Award. Her research was supported by the NWO VIDI, NWO-XL, ERC starting grant, CancerGenomics.nl, EMBO long-term fellowships, KWF fellowship for basic research, the NWO Toptalent Program and Huygens Scholarship Talent Program.
Awards
2023: EMBO young investigator programme (European Molecular Biology Organization)
2022: NWO-XL
2022: NWO VIDI
2020: KNAW early career award (Royal Netherlands Academy of Arts and Sciences)
2018: NVBMB prize (Netherlands Organization for Biochemistry and Molecular Biology)
2017: ERC starting grant
2017: CancerGenomiCs.nl gravitation project
2015: NCI Director's Innovation Award
2015: Fellows Award for Research Excellence
2012: KWF (Dutch Cancer Society) fellowship for basic research
2012: European Molecular Biology Organization (EMBO) long-term fellowship
2011: “Cancer Genomics and Developmental Biology” PhD Student Award, Utrecht University
2008: NWO Toptalent Program
2007: Huygens Scholarship Program
Key Publications
Brouwer I, Kerklingh E, van Leeuwen F, Lenstra TL. Dynamic epistasis analysis reveals how chromatin remodeling regulates transcriptional bursting. In press at Nature Structural and Molecular Biology. bioRxiv 2021.12.15.472793; doi: https://doi.org/10.1101/2021.12.15.472793.
Patel HP, Coppola S, Pomp W, Brouwer I, Lenstra TL. DNA supercoiling restricts the transcriptional bursting of neighboring eukaryotic genes. bioRxiv 2022.03.04.482969v1; doi: https://doi.org/10.1101/2022.0...
Donovan BT, Huynh A, Ball DA, Patel HP, Poirier MG, Larson DR, Ferguson ML*, Lenstra TL*. Live-cell imaging reveals the interplay between transcription factors, nucleosomes, and bursting. EMBO Journal. 2019 Jun 17;38(12). PMID: 31101674 *These authors contributed equally
de JongeWJ, Patel HP, Meeussen JVW, Lenstra TL. Following the tracks: how transcription factor binding dynamics control transcription. Biophysical Journal. 2022 May 3;121(9):1583-1592. doi: 10.1016/j.bpj.2022.03.026. Epub 2022 Mar 23.
Brouwer I, Lenstra TL. Visualizing transcription: key to understanding gene expression dynamics. Current Opinion in Chemical Biology. 2019 Aug;51:122-129. PMID: 31284216
Lenstra TL, Coulon A, Chow CC, Larson DR. Single-molecule imaging reveals a switch between spurious and functional ncRNA transcription. Molecular Cell. 2015 Nov 19;60(4):597-610. PMID: 26549684.
Lenstra TL, Benschop JJ, Kim T, Schulze JM, Brabers NA, Margaritis T, van de Pasch LA, van Heesch SA, Brok MO, Groot Koerkamp MJ, Ko CW, van Leenen D, Sameith K, van Hooff SR, Lijnzaad P, Kemmeren P, Hentrich T, Kobor MS, Buratowski S, Holstege FCP. The specificity and topology of chromatin interaction pathways in yeast. Molecular Cell. 2011 May 20;42(4):536-49. PMID: 21596317.
Members
| Tineke Lenstra Group leader | Lotte de van der Schueren PhD candidate | Carolien Bastiaanssen PostDoc |
| Charis Fountas PhD student | Demi Blüm PhD | Gert-Jan Kuijntjes PhD student |
| Jos Meeussen PhD Student | Rein Hoogstraaten Technician | Veer Keizer Postdoc |
| Wim Pomp Research assistant |