Dr. R.A.F. (Rutger) Gjaltema

The Gjaltema Lab

Exploring Epigenetic Mechanisms Shaping Cell Identity Formation and Dissolution

In the course of embryonic development, pluripotent embryonic stem cells undergo differentiation into specific lineages, acquiring distinctive gene expression patterns for each cell type. This process is orchestrated by an activating epigenetic landscape at genes essential for cell type-specific expression networks. Simultaneously, the expression of undesirable genes is repressed.

Conversely, in various inflammatory diseases, somatic cells exhibit increased plasticity in their identity, creating a opportunity for transdifferentiation into other cell types. This phenomenon can disturb the delicate balance of healthy tissue homeostasis.

Our research is focused on unraveling the intricate details of this process. We are particularly interested in understanding which regulatory factors converge at the chromatin level and the temporal sequence in which they respond to environmental signals. Additionally, we aim to explore how genomic loci integrate this information, leading to alterations in the expression patterns of cell identity genes. This knowledge holds significant implications for deciphering the pathogenesis of diseases and has promising applications in the field of regenerative medicine.

Projects

In somatic cells, the identity of a cell is often denoted by broad linear distributions of H3K4me3 and H3K79me2 histone marks at the promoter region. In contrast, essential (housekeeping) genes lack such patterns. These domains correspond to a high level of transcriptional consistency in the underlying genes, characterized by frequent bursts of transcription and a reduced degree of pausing by the transcription machinery near the promoter.

Recent studies highlight the significance of H3K79me2 as an epigenetic safeguard against the loss of cell identity. For terminally differentiated somatic cells, maintaining this epigenetic mark is crucial for preserving their specific cellular identity. Interestingly, inhibiting the enzyme responsible for H3K79me2 (DOT1L) has been shown to enhance the reprogramming efficiency of inducible pluripotent stem cells. Additionally, it contributes to the acquisition of stemness in cancer cells, a hallmark of cancer.

Our research is centered on understanding the intricate interplay of these processes. We aim to unravel how these epigenetic mechanisms collaborate to regulate cellular memory at the intersection of stemness, providing insights into the regulation of cell identity.

Our Toolbox

We are a technological driven lab that applies cutting-edge technologies to measure transcription and epigenetic parameters, generate novel molecular tools to simulate epigentic memory or spatio-temporal depletion of epigenetic enzymes, and perform CRISPR screens to indentify novel regulators of in gene regulatory processes.

We apply these tools in several cellular model systems to answer these fundamental questions: mouse embryonic stem cells that are subjected to various differentiation conditions, human cancer cells, and human primary cells.

We frequently have opportunities for BSc and MSc students to join our lab and get trained in various disciplines in ongoing projects. As availability is limited, please reach out to us well in advance for more details via r.a.f.gjaltema@uva.nl

Current members

Judith Portillo Bescos (Bsc, University of Barcelona, Erasmus) | February 2024 -

Tjomme Nauta (MSc, University of Amsterdam | December 2023 -

Quint van Loosen (PhD candidate; copromoter with Prof. Dr. Verschure)

Anna van den Berg van Saparoea (Research technician; co-supervisor with Prof. Dr. Verschure)

Alumni

Sofia Moreno Hoffmann (MSc, University of Amsterdam) | January - October 2023

Jip van der Heijden (BSc, Radboud University Nijmegen) | Februari - June 2023

Rutger Gjaltema earned his Ph.D. with honors from the University of Groningen, the Netherlands (2011-2016) with the thesis titled 'Modifications of collagen and chromatin in ECM-related disease: Uncovering therapeutic targets for fibrosis and cancer.' During this period, he concentrated on the epigenetic regulation of genes in fibrosis and cancer. Specifically, he developed epigenome editing tools to regulate PLOD2 expression in cancer cells and fibrotic fibroblasts. Additionally, he unraveled several molecular mechanisms governing fibrosis and Bruck syndrome. This research was conducted in the labs of Prof. Dr. Marianne Rots and Prof. Dr. Ruud Bank at the University Medical Center Groningen.

For his postdoctoral period (2016-2022), Rutger joined the lab of Dr. Edda Schulz at the Max Planck Institute for Molecular Genetics in Berlin, Germany. There, he investigated the cis-regulatory landscape of X-chromosome inactivation during early embryonic development. His research identified insights into the regulation of Xist, a crucial player in X-chromosome inactivation in females. Importantly, he discovered a new long non-coding RNA locus (Xert) with a superenhancer, acting as the primary cis-regulatory cue for Xist and influencing random X-chromosome inactivation in mouse embryonic stem cells.

In 2022, Rutger took on the position of Assistant Professor of Epigenetics in the Molecular & Cellular Epigenetics group at the Swammerdam Institute for Life Sciences, University of Amsterdam. In this role, he dedicates his time to both research and teaching across various programs within the Faculty of Science (UvA).

Publications

refereed (13)

2023

Noviello, G., Gjaltema, R. A. F., & Schulz, E. G. (2023). CasTuner is a degron and CRISPR/Cas-based toolkit for analog tuning of endogenous gene expression. Nature Communications, 14(1), 3225. https://doi.org/10.1038/s41467-023-38909-4

2022

Gjaltema, R. A. F., Schwämmle, T., Kautz, P., Robson, M., Schöpflin, R., Ravid Lustig, L., Brandenburg, L., Dunkel, I., Vechiatto, C., Ntini, E., Mutzel, V., Schmiedel, V., Marsico, A., Mundlos, S., & Schulz, E. G. (2022). Distal and proximal cis-regulatory elements sense X chromosome dosage and developmental state at the Xist locus. Molecular Cell, 82(1), 190-208.e17. https://doi.org/10.1016/j.molcel.2021.11.023

2021

Vanchin, B., Sol, M., Gjaltema, R. A. F., Brinker, M., Kiers, B., Pereira, A. C., Harmsen, M. C., Moonen, J.-R. A. J., & Krenning, G. (2021). Reciprocal regulation of endothelial-mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease. Scientific Reports, 11(1), 17764. https://doi.org/10.1038/s41598-021-97127-4

2020

Gjaltema, R. A. F., & Rots, M. G. (2020). Advances of epigenetic editing. Current opinion in chemical biology, 57, 75-81. https://doi.org/10.1016/j.cbpa.2020.04.020

2018

Gjaltema, R. A. F., & Schulz, E. G. (2018). CRISPR/dCas9 Switch Systems for Temporal Transcriptional Control. Methods in molecular biology (Clifton, N.J.), 1767, 167-185. https://doi.org/10.1007/978-1-4939-7774-1_8

2017

Gjaltema, R. A. F., & Bank, R. A. (2017). Molecular insights into prolyl and lysyl hydroxylation of fibrillar collagens in health and disease. Critical Reviews in Biochemistry and Molecular Biology, 52(1), 74-95. https://doi.org/10.1080/10409238.2016.1269716
Leus, N. G. J., van den Bosch, T., van der Wouden, P. E., Krist, K., Ourailidou, M. E., Eleftheriadis, N., Kistemaker, L. E. M., Bos, S., Gjaltema, R. A. F., Mekonnen, S. A., Bischoff, R., Gosens, R., Haisma, H. J., & Dekker, F. J. (2017). HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice. Scientific Reports, 7, 45047. https://doi.org/10.1038/srep45047
Piersma, B., Wouters, O. Y., de Rond, S., Boersema, M., Gjaltema, R. A. F., & Bank, R. A. (2017). Ascorbic acid promotes a TGFβ1-induced myofibroblast phenotype switch. Physiological Reports, 5(17). https://doi.org/10.14814/phy2.13324
Song, J., Cano-Rodriquez, D., Winkle, M., Gjaltema, R. A. F., Goubert, D., Jurkowski, T. P., Heijink, I. H., Rots, M. G., & Hylkema, M. N. (2017). Targeted epigenetic editing of SPDEF reduces mucus production in lung epithelial cells. American journal of physiology. Lung cellular and molecular physiology, 312(3), L334-L347. https://doi.org/10.1152/ajplung.00059.2016

2016

Cano-Rodriguez, D., Gjaltema, R. A. F., Jilderda, L. J., Jellema, P., Dokter-Fokkens, J., Ruiters, M. H. J., & Rots, M. G. (2016). Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner. Nature Communications, 7, 12284. https://doi.org/10.1038/ncomms12284
Gjaltema, R. A. F., van der Stoel, M. M., Boersema, M., & Bank, R. A. (2016). Disentangling mechanisms involved in collagen pyridinoline cross-linking: The immunophilin FKBP65 is critical for dimerization of lysyl hydroxylase 2. Proceedings of the National Academy of Sciences of the United States of America, 113(26), 7142-7. https://doi.org/10.1073/pnas.1600074113

2015

Gjaltema, R. A. F., de Rond, S., Rots, M. G., & Bank, R. A. (2015). Procollagen Lysyl Hydroxylase 2 Expression Is Regulated by an Alternative Downstream Transforming Growth Factor β-1 Activation Mechanism. The Journal of Biological Chemistry, 290(47), 28465-28476. https://doi.org/10.1074/jbc.M114.634311
Maleszewska, M., Gjaltema, R. A. F., Krenning, G., & Harmsen, M. C. (2015). Enhancer of zeste homolog-2 (EZH2) methyltransferase regulates transgelin/smooth muscle-22α expression in endothelial cells in response to interleukin-1β and transforming growth factor-β2. Cellular Signalling, 27(8), 1589-1596. https://doi.org/10.1016/j.cellsig.2015.04.008

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