Dr. K.S. (Kerstin) Wendt

Multiple mechanisms safeguard genome stability and ensure precise temporal and spatial control of gene activity. The cohesin complex and its associated accessory proteins and regulators are central to these processes since cells use those proteins as versatile tools to organize and dynamically shape chromatin within the nucleus (more on cohesin functions below). Mutations or misexpression of cohesin family proteins has severe consequences and are associated with cancer and developmental defects.

We want to understand how the specific mutations in cohesin and cohesin regulators cause the developmental defects observed in Cornelia de Lange Syndrome (CdLS) and related syndromes (more on CdLS and our CdLS research below).

To gain understanding of the molecular mechanisms underlying the specific functions of the cohesin family proteins, we investigate how different subunits steer the fate of individual cohesin complexes.

To this we use a wide range of methodologies (biochemistry, imaging, genomics and proteomics) and different cellular models ranging from CRISPR-engineered cell lines that allow rapid protein depletion to primary patient-derived cells and induced pluripotent stem cells that we differentiate into brain organoids (collaboration with the Debbie van den Berg lab) and into neuronal cell types.

Close collaborations with clinicians taking care of CdLS patients at the Dutch and German CdLS Reference Centers and other international institutes are essential for our work. In long-standing collaborations, we could contribute to improving the diagnostic of CdLS by identifying novel CdLS genes.

Equally important is our involvement with families and caretakers form the Dutch CdLS family organization and the CdLS World organisation (https://www.cdlsworld.org/). These interactions strongly motivate our research, and we hope to contribute with our fundamental research to the improvement or discovery of therapeutic options.

In a nutshell - Cohesin and NIPBL/MAU2 kollerin functions

The cohesin multi-subunit complex has the unique capability to tether DNA strands, either two different DNA strands (trans) or connect two distant regions on the same strand (cis) by forming chromatin loops. Cohesin-mediated trans interactions are crucial for sister chromatid cohesion and chromosome segregation during cell division but also assist with DNA double strand break repair. Cohesin generates chromatin loops by ATP-hydrolysis-driven translocation of the complex along the chromatin strand called “loop-extrusion”. Cohesin-mediated loops contribute to the compartmentalization of the genome (TADs) and can facilitate/prevent contacts between promoters and gene regulatory elements (e.g. enhancers). The activity of cohesin along chromatin strands impacts other chromatin-associated processes like DNA replication and transcription but is also influenced by them.

 

The NIPBL/MAU2 heterodimer, also termed kollerin, was initially identified as cohesin-loader but was recently found to be important for loop extrusion and to be integral part of the cohesin complex. However, NIPBL/MAU2 have also functions that are independent from cohesin. We and others have shown in the past that NIPBL/MAU2 is important for gene activity and binds at promoters and enhancers. The heterodimer is critical for the mutual stability of the proteins, and whether MAU2 has additional functions next to stabilizing NIPBL as chaperone remains to be investigated.     

NIPBL/MAU2 mutations cause Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes

Cornelia de Lange syndrome (CdLS), a developmental syndrome occurring in 1 of 20.000 births with a broad clinical spectrum that is marked by very characteristic facial features, growth delay, limb anomalies and cognitive impairment. Variants in NIPBL account for ~70% of cases while variants in SMC1A, SMC3, RAD21, MAU2 and HDAC8 account for 10–15% of cases. Interestingly, variants in the STAG subunits of cohesin (STAG1, STAG2 and the meiosis-specific STAG3) do show phenotypes that have only little overlap with CdLS.

Interestingly, the characteristic CdLS phenotype is occasionally observed associated with variants of other chromatin regulators like ANKRD11, AFF4, BRD4, SETD5, TAF1, TAF6, ZMYND11, PHIP, and MED13L. Why we observe these overlaps in phenotypes is an exciting open question.

The most severely affected cases have NIPBL variants causing haploinsufficiency. Therefore we focus in our current projects on investigating how NIPBL haploinsufficincy affect neuronal development.

 

Research questions in ongoing projects

Interested in a research project bridging fundamental research and clinical research? We are always looking for motivated students for Master or Bachelor internships. Get in contact if one of these projects interests you! (Kerstin S. Wendt: k.wendt@erasmusmc.nl)

• How does NIPBL haploinsufficiency impact neuronal development at a molecular and tissue level (Collaboration with Debbie van den Berg)?
• In about 10% of cases CdLS mutations affect only a part of the cells in the body (mosaicism). How do healthy and mutant cells interact/compete during neuronal development? – Modelling of NIPBL mosaicism in brain organoids (Collaboration with Debbie van den Berg).
• Cohesin’s STAG subunits determine specifics of cohesin functions. What happens when one of the STAG orthologs is absent or carries mutations? – Investigating the different cohesin functions in patient cells and rapid protein depletion models.
• Cohesin-independent functions of NIPBL and MAU2. What can specific interactors of NIPBL and MAU2 tell us about these functions, and can we learn something about CdLS-overlapping syndromes? – Mapping and testing interactors of NIPBL and MAU2 with proteomics.
• Cohesin and NIPBL/MAU2 are very abundant on chromatin and interact with DNA replication, DNA damage repair and transcription. Which of those processes depend on cohesin loop extrusion or more on NIPBL functions?

Long-term collaborations:

• Debbie van den Berg, Department of Developmental Biology, Erasmus MC, Rotterdam
• Frank Kaiser and Ilaria Parenti, Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
• Sylvia Huisman and Leonie Menke, Department of Pediatrics, Amsterdam University Medical Center - Emma Children's Hospital, Amsterdam
• Akis Papantonis, University of Goettingen, Germany

Funding

NWO, ZonMW, E-RARE, KWF, DFG/TRR81

During her PhD as structural biologist Kerstin S. Wendt solved the first protein crystal structure of a component of the APC/C complex, an important cell cycle regulator. This work raised her interest in cell cycle regulators and in particular in proteins that can organize DNA strands. During her PostDoc in the group of Jan-Michael Peters at the IMP in Vienna/Austria she discovered a novel condensin complex (condensin II). Further she determined in one of the first genome-wide mapping studies the position of the cohesin complex in the human genome. These studies lead to the discovery that the cohesin complex, well known to promote chromosome cohesion, cooperates with the chromatin insulator CTCF for chromatin insulation and transcriptional regulation. Shortly after she could show that the cohesin complex is involved in promoting long-range interactions of the chromatin fibre.
With her own research group, which she started in 2009 at the Erasmus MC, she investigates, which roles cohesin and CTCF have for shaping the overall structure of the chromatin fibre. Among the approaches used in her group are different chromatin conformation capturing techniques and imaging techniques such as DNA-FISH. The group is together with other groups at the department of Cell biology involved in the development of novel high resolution capture techniques.
Next to the interest in chromatin organization Kerstin S. Wendt has a strong interested in the developmental syndrome Cornelia de Lange Syndrome which is associated with mutations in cohesin complex subunits or cohesin regulators. In a consortium with several international partners she investigates how these mutations lead to the malformations observed in this congenital disorder. 

Contact: Kerstin S. Wendt
Telephone: +31-107044007
E-mail: k.wendt@erasmusmc.nl 

2026
Parenti I, Hesters A, Gil-Salvador M, Duffy L, Kanber D, Beygo J, Kerkhof J, Steenpaß L, Leitão E, Woestefeld J, Boone PM, Kao EM, Alabdi L, Aldhalaan HM, Alkuraya FS, Alshammari MJ, Antonarakis SE, Basel D, Cassinari K, de Polli Cellin L, Clause AR, de Lima Jorge AA, de Castro Leal A, Collins SC, Durand B, Eckhold J, Hashem MO, Jayakar P, Khan AO, Kato K, Kubica R, Lyon GJ, Marchi E, McCarrier J, Kimmig LK, Mizuno S, Nicolas G, Nishio Y, Ogi T, Pié J, Prell J, Puisac B, Ramos FJ, Ranza E, Redin C, Rush E, Saitoh S, Shamseldin HE, Starling S, Astiazaran-Symonds E, Eltahir SH, Kuechler A, Sadikovic B, Yalcin B, Wendt KS, Kaiser FJ. Pathogenic variants in the cohesin loader subunit MAU2 underlie a distinct Cornelia de Lange Syndrome subtype. Nat Commun. 2026 Mar 30;17(1):3036. doi: 10.1038/s41467-026-71177-6.

van Staalduinen J, Kabbech H, Yavuz S, Cetin R, Loda A, van Cappellen W, Houtsmuller A, Wendt KS, Smal I, Grosveld F. Chromatin dynamics of the Klf4 locus in mouse pluripotent cells Sci Rep 16, 10941 (2026). https://doi.org/10.1038/s41598-026-45230-9

2025
Moronta Gines M, Wessels MW, Casa V, van Staveren T, Hof A, Chung WK, Willems M, Sandestig A, Huening I, Turnpenny P, Lefebvre M, Parenti I, Kaiser FJ, Demmers J, van Ijcken WFJ, Wendt KS. STAG2-truncating variants reveal a mosaic STAG2 inactivation pattern and compensatory mechanisms involving cohesin complex remodeling. iScience. 2025 Nov 22;28(12):114195. doi:10.1016/j.isci.2025.114195.

2023
Hollstein R, Peron A, Wendt KS, Parenti I. Editorial: Pathogenic mechanisms in neurodevelopmental disorders: advances in cellular models and multi-omics approaches. Front Cell Dev Biol. 2023 Oct 6;11:1296885. doi:10.3389/fcell.2023.1296885. 

van Schie JJM, de Lint K, Molenaar TM, Moronta Gines M, Balk JA, Rooimans MA, Roohollahi K, Pai GM, Borghuis L, Ramadhin AR, Corazza F, Dorsman JC, Wendt KS, Wolthuis RMF, de Lange J. CRISPR screens in sister chromatid cohesion defective cells reveal PAXIP1-PAGR1 as regulator of chromatin association of cohesin. Nucleic Acids Res. 2023 Oct 13;51(18):9594-9609. doi: 10.1093/nar/gkad756. 

van Staalduinen J, van Staveren T, Grosveld F, Wendt KS. Live-cell imaging of chromatin contacts opens a new window into chromatin dynamics. Epigenetics Chromatin. 2023 Jun 23;16(1):27. doi: 10.1186/s13072-023-00503-9. 

2022
Gines MM, Wendt KS. A Robust Protocol for Investigating the Cohesin Complex by ChIP-Sequencing. Methods Mol Biol. 2022;2458:113-122. doi:10.1007/978-1-0716-2140-0_7. 

2021
Zhang S, Übelmesser N, Josipovic N, Forte G, Slotman JA, Chiang M, Gothe HJ, Gusmao EG, Becker C, Altmüller J, Houtsmuller AB, Roukos V, Wendt KS, Marenduzzo D, Papantonis A. RNA polymerase II is required for spatial chromatin reorganization following exit from mitosis. Sci Adv. 2021 Oct 22;7(43):eabg8205. doi: 10.1126/sciadv.abg8205. 

2020
Parenti I, Diab F, Gil SR, Mulugeta E, Casa V, Berutti R, Brouwer RWW, Dupé V, Eckhold J, Graf E, Puisac B, Ramos F, Schwarzmayr T, Gines MM, van Staveren T, van IJcken WFJ, Strom TM, Pié J, Watrin E, Kaiser FJ, Wendt KS. MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome. Cell Rep. 2020 May 19;31(7):107647. doi:10.1016/j.celrep.2020.107647.

Casa V, Moronta Gines M, Gade Gusmao E, Slotman JA, Zirkel A, Josipovic N, Oole E, van IJcken WFJ, Houtsmuller AB, Papantonis A, Wendt KS. Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control. Genome Res. 2020 Apr;30(4):515-527. doi: 10.1101/gr.253211.119.

2019
Kruszka P, Berger SI, Casa V, Dekker MR, Gaesser J, Weiss K, Martinez AF, Murdock DR, Louie RJ, Prijoles EJ, Lichty AW, Brouwer OF, Zonneveld-Huijssoon E, Stephan MJ, Hogue J, Hu P, Tanima-Nagai M, Everson JL, Prasad C, Cereda A, Iascone M, Schreiber A, Zurcher V, Corsten-Janssen N, Escobar L, Clegg NJ, Delgado MR, Hajirnis O, Balasubramanian M, Kayserili H, Deardorff M, Poot RA, Wendt KS, Lipinski RJ, Muenke M. Cohesin complex-associated holoprosencephaly. Brain. 2019 Sep 1;142(9):2631-2643. doi: 10.1093/brain/awz210. 

Moronta-Gines M, van Staveren TRH, Wendt KS. One ring to bind them - Cohesin's interaction with chromatin fibers. Essays Biochem. 2019 Apr 23;63(1):167-176. doi: 10.1042/EBC20180064.

2018
Kolovos P, Brouwer RWW, Kockx CEM, Lesnussa M, Kepper N, Zuin J, Imam AMA, van de Werken HJG, Wendt KS, Knoch TA, van IJcken WFJ, Grosveld F. Investigation of the spatial structure and interactions of the genome at sub-kilobase-pair resolution using T2C. Nat Protoc. 2018 Mar;13(3):459-477. doi: 10.1038/nprot.2017.132. Epub 2018 Feb 8. 

2017
Zuin J, Casa V, Pozojevic J, Kolovos P, van den Hout MCGN, van Ijcken WFJ, Parenti I, Braunholz D, Baron Y, Watrin E, Kaiser FJ, Wendt KS. Regulation of the cohesin-loading factor NIPBL: Role of the lncRNA NIPBL-AS1 and identification of a distal enhancer element. PLoS Genet. 2017 Dec 20;13(12):e1007137. doi: 10.1371/journal.pgen.1007137. 

Pozojevic J, Parenti I, Graul-Neumann L, Ruiz Gil S, Watrin E, Wendt KS, Werner R, Strom TM, Gillessen-Kaesbach G, Kaiser FJ. Novel mosaic variants in two patients with Cornelia de Lange syndrome. Eur J Med Genet. 2017 Nov 15. pii: S1769-7212(17)30498-6. doi: 10.1016/j.ejmg.2017.11.004. 

Nozaki T, Imai R, Tanbo M, Nagashima R, Tamura S, Tani T, Joti Y, Tomita M, Hibino K, Kanemaki MT, Wendt KS, Okada Y, Nagai T, Maeshima K. Dynamic Organization of Chromatin Domains Revealed by Super-Resolution Live-Cell Imaging. Mol Cell. 2017 Jul 20;67(2):282-293.e7. doi: 10.1016/j.molcel.2017.06.018. Epub 2017 Jul 14. 

2016
Watrin E, Kaiser FJ, Wendt KS. Gene regulation and chromatin organization: relevance of cohesin mutations to human disease. Curr Opin Genet Dev. 2016 Apr;37:59-66. doi: 10.1016/j.gde.2015.12.004. Epub 2016 Jan 25. 

Knoch TA, Wachsmuth M, Kepper N, Lesnussa M, Abuseiris A, Ali Imam AM, Kolovos P, Zuin J, Kockx CEM, Brouwer RWW, van de Werken HJG, van IJcken WFJ, Wendt KS, Grosveld FG. The detailed 3D multi-loop aggregate/rosette chromatin architecture and functional dynamic organization of the human and mouse genomes. Epigenetics Chromatin. 2016 Dec 24;9:58. doi: 10.1186/s13072-016-0089-x. eCollection 2016. 

Parenti I, Gervasini C, Pozojevic J, Wendt KS, Watrin E, Azzollini J, Braunholz D, Buiting K, Cereda A, Engels H, Garavelli L, Glazar R, Graffmann B, Larizza L, Lüdecke HJ, Mariani M, Masciadri M, Pié J, Ramos FJ, Russo S, Selicorni A, Stefanova M, Strom TM, Werner R, Wierzba J, Zampino G, Gillessen-Kaesbach G, Wieczorek D, Kaiser FJ. Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction. Clin Genet. 2016 May;89(5):564-73. doi: 10.1111/cge.12717. Epub 2016 Jan 25. 

2015
Parenti I, Gervasini C, Pozojevic J, Graul-Neumann L, Azzollini J, Braunholz D, Watrin E, Wendt KS, Cereda A, Cittaro D, Gillessen-Kaesbach G, Lazarevic D, Mariani M, Russo S, Werner R, Krawitz P, Larizza L, Selicorni A, Kaiser FJ. Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype. Clin Genet. 2015 Feb 4. doi: 10.1111/cge.12564. 

Braunholz D., Obieglo C., Parenti, I., Pozojevic J., Eckhold J., Reiz, B., Braenne I., Wendt KS, Watrin E., Vodopiutz J., Rieder H., Gillessen-Kaesbach G., Kaiser F.J. Hidden Mutations in CdLS - Limitations of Sanger Sequencing in Molecular Diagnostics. Hum Mutat. 2015 Feb;36(2):279-80. 

2014
Kolovos P, van de Werken HJ, Kepper N, Zuin J, Brouwer RW, Kockx CE, Wendt KS, van IJcken WF, Grosveld F, Knoch TA. Targeted Chromatin Capture (T2C): a novel high resolution high throughput method to detect genomic interactions and regulatory elements. Epigenetics Chromatin. 2014 Jun 16;7:10. doi: 10.1186/1756-8935-7-10. 

Wendt KS, Grosveld FG. Transcription in the context of the 3D nucleus. Curr Opin Genet Dev. 2014 Apr;25:62-7. 

Zuin J, Dixon JR, van der Reijden MI, Ye Z, Kolovos P, Brouwer RW, van de Corput MP, van de Werken HJ, Knoch TA, van IJcken WF, Grosveld FG, Ren B, Wendt KS. Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):996-1001. 

Braunholz D, Obieglo C, Parenti I, Pozojevic J, Eckhold J, Reiz B, Braenne I, Wendt KS, Watrin E, Vodopiutz J, Rieder H, Gillessen-Kaesbach G, Kaiser FJ. Hidden Mutations in CdLS - Limitations of Sanger Sequencing in Molecular Diagnostics. Hum Mutat. 2014 Sep 5. doi: 10.1002/humu.22685. 

Kolovos P, van de Werken HJ, Kepper N, Zuin J, Brouwer RW, Kockx CE, Wendt KS, van IJcken WF, Grosveld F, Knoch TA. Targeted Chromatin Capture (T2C): a novel high resolution high throughput method to detect genomic interactions and regulatory elements. Epigenetics Chromatin. 2014 Jun 16;7:10. 

2013
Zuin J, Franke V, van Ijcken WF, van der Sloot A, Krantz ID, van der Reijden MI, Nakato R, Lenhard B, Wendt KS. A cohesin-independent role for NIPBL at promoters provides insights in CdLS. PLoS Genet. 2014 Feb 13;10(2):e1004153. Epub Dec. 2013 

Stadhouders R, Kolovos P, Brouwer R, Zuin J, van den Heuvel A, Kockx C, Palstra RJ, Wendt KS, Grosveld F, van Ijcken W, Soler E. Multiplexed chromosome conformation capture sequencing for rapid genome-scale high-resolution detection of long-range chromatin interactions. Nat Protoc. 2013 Mar;8(3):509-24. 

2009
Nativio R, Wendt KS, Ito Y, Huddleston JE, Uribe-Lewis S, Woodfine K, Krueger C, Reik W, Peters JM, Murrell A. Cohesin is required for higher-order chromatin conformation at the imprinted IGF2-H19 locus. PLoS Genet. 2009 Nov;5(11):e1000739. 

Wendt KS, Peters JM. How cohesin and CTCF cooperate in regulating gene expression. Chromosome Res. 2009;17(2):201-14. 

2008
Wendt KS, Yoshida K, Itoh T, Bando M, Koch B, Schirghuber E, Tsutsumi S, Nagae G, Ishihara K, Mishiro T, Yahata K, Imamoto F, Aburatani H, Nakao M, Imamoto N, Maeshima K, Shirahige K, Peters JM. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature. 2008 Feb 14;451(7180):796-801. 

Koch B, Kueng S, Ruckenbauer C, Wendt KS, Peters JM. The Suv39h-HP1 histone methylation pathway is dispensable for enrichment and protection of cohesin at centromeres in mammalian cells. 
Chromosoma. 2008 Apr;117(2):199-210. doi: 10.1007/s00412-007-0139-z.

2003
Yeong FM, Hombauer H, Wendt KS, Hirota T, Mudrak I, Mechtler K, Loregger T, Marchler-Bauer A, Tanaka K, Peters JM, Ogris E. Identification of a subunit of a novel Kleisin-beta/SMC complex as a potential substrate of protein phosphatase 2A. Curr Biol. 2003 Dec 2;13(23):2058-64. doi: 10.1016/j.cub.2003.10.032.

Wendt KS, Schall I, Huber R, Buckel W, Jacob U. Crystal structure of the carboxyltransferase subunit of the bacterial sodium ion pump glutaconyl-coenzyme A decarboxylase. EMBO J. 2003 Jul 15;22(14):3493-502. doi: 10.1093/emboj/cdg358.

2001
Wendt KS, Vodermaier HC, Jacob U, Gieffers C, Gmachl M, Peters JM, Huber R, Sondermann P. Crystal structure of the APC10/DOC1 subunit of the human anaphase-promoting complex. Nat Struct Biol. 2001 Sep;8(9):784-8. doi: 10.1038/nsb0901-784.

Cohesin functions and malfunctions

Genetic information in the form of the chromatin fiber is tightly packed into the nuclei of eukaryotic cells. To allow cellular functions the genetic information needs to be read out by the transcription machinery, duplicated by the replication machinery and the copies need to be identified and distributed correctly during cell division.
Cohesin is a ring-shaped protein complex critical to structure and handle the chromatin fiber during these processes. Defects in cohesin function can lead to chromosomal instability, gene expression defects and as consequence cancer and defects during embryonic development.
It is very important to understand the molecular mechanism of the cohesin complex to understand how mutations in the complex lead to disease. Great progress has been made in the past years and novel functions of cohesin have been uncovered. However, a number of fundamental questions are still unsolved. Some of these questions are outlined below.

If you look for an exciting project for your Bachelor and Master please contact us. The projects are suitable for students from the Molecular Medicine program, the Nanobiology program but also other master programs.

Bachelor and Master projects

Visualize cohesin dependent chromatin organization and respective changes after cohesin depletion using STORM and SIM imaging.

How many cohesin rings are necessary to form a loop?

How do the cohesin/CTCF binding sites that form the loop find each other?

According to the “loop extrusion model” cohesin actively pulls DNA through its protein ring. Can we prove/disprove this model?

During cell division chromatin is condensed into very compact metaphase chromosomes and cohesin is completely removed from chromatin. How are cohesin and CTCF sites reestablished after mitosis?

Cohesin & Disease – How do mutations observed in patients with severe developmental defects affect the functioning of the cohesin complex?

For details concerning the projects please contact k.wendt@erasmusmc.nl.

To approach these questions we use a wide panel of methodologies:

Imaging – Immunofluorescence staining, live cell imaging, STORM and SIM microscopy
Chromatin methods – ChIP, CHIP-sequencing and data analysis, chromatin conformation capturing techniques (4C, T2C, HiC)
Cell biology methods – CRISPR editing, manipulation of chromatin using dCAS9 (with tags), knockdown of proteins using siRNA
Biochemistry – Immunoprecipitation, Western blotting, antibody production and purification, mass spectrometry
Development of new methodology - Methods to study protein-chromatin interactions in a time-resolved manner

Master projects:	Please inquire with us about current projects available
PhD positions:	None
Postdoc positions:	None

 

Contact: Kerstin S. Wendt
Telephone: +31-107044007
E-mail: k.wendt@erasmusmc.nl 

People:

Francesco Corazza, PhD student
Amber Hof, PhD student

Alternating master students and HBO students. 

Kerstin S. Wendt
Telephone: +31-107044007
E-mail: k.wendt@erasmusmc.nl 

Visiting address
Dept. of Developmental Biology
Erasmus MC
Faculty building
Room Ee-1032
Wytemaweg 80
3015CN Rotterdam 
The Netherlands

Mail address
Dept. of Developmental Biology
Erasmus MC
Room Ee-1032
PO Box 2040
3000 CA Rotterdam
The Netherlands