Our Discoveries

Borsellini et al., bioRxiv, 2024

Switching on condensin

In a fabulous three-way collaboration with the Vannini and Musacchio labs, we discover what activates condensin as cells enter mitosis, and also what keeps the genome uncondensed during interphase. We find that M18BP1 binds condensin II to initiate condensation. MCPH1 keeps the interphase genome in its uncompacted state by outcompeting M18BP1 binding. The switch from MCPH1 to M18BP1 triggers chromosome condensation.

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García-Nieto et al., Nature Struct. & Mol. Biol., 2023

A molecular code that shapes our genome

In a fantastic collaboration with Daniel Panne's lab, we discovered how a molecular code embedded in our proteins determines the shape of our our DNA. We reveal how a universal mechanism directs the loops that shape our interphase genome, and also connects the sister chromatids at centromeres, thus providing a molecular explanation for the well-known X-shape of our chromosomes.

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van Ruiten et al., Nature Struct. & Mol. Biol., 2022

A brake for the looping cycle

The acetylation of cohesin’s SMC3 subunit is a dynamic process that involves the acetyltransferase ESCO1 and deacetylase HDAC8. We show that this cohesin acetylation cycle controls the 3D genome by converting cohesin into a PDS5-bound state. We suggest that PDS5 acts as a brake that enables the pausing and restart of loop enlargement. The cohesin acetylation cycle hereby provides punctuation in the process of genome folding.

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Haarhuis et al., Nature Communications, 2022

Keeping heterochromatin in check

The genome consists of regions of transcriptionally active euchromatin and more silent heterochromatin. In a fantastic collaboration with the lab of Elzo de Wit, we reveal that the formation of heterochromatin domains requires cohesin turnover on DNA. We suggest that the Mediator-CDK module contributes to gene expression by limiting the formation of dense heterochromatin domains.

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Hoencamp et al., Science, 2021

Condensin II as a determinant of architecture type

In an incredible collaboration with the labs of Erez Lieberman Aiden, Jose Onuchic, Michele di Pierro, multiple NKI-based groups, and the DNA Zoo consortium, we study chromosome-scale genome folding across the eukaryotic tree of life. The absence of condensin II subunits turns out to correlate with the type of nuclear architecture. Depletion of condensin II in human cells transforms the folding of the human genome into a state as found in mosquitoes and fungi.

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Li et al., Nature, 2020

Genome folding by cohesin & CTCF

Cohesin folds the genome into loops that are anchored by CTCF. In a great collaboration with the lab of Daniel Panne, we show that the interaction of the CTCF N-terminus with the SA2-SCC1 subunits of cohesin stabilises cohesin at CTCF sites. This interaction is essential for CTCF-anchored loops genome-wide. We propose that CTCF enables chromatin loop formation by protecting cohesin against loop release.

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Elbatsh et al., Mol Cell, 2019

Condensin exhibits self-restraint

Chromosome condensation by condensin is essential for mitosis. In a wonderful collaboration with colleagues from Delft and Heidelberg, we find that one of condensin's ATPase sites promotes the initiation of loops, while the other site determines the type of loops that condensin forms. Mutation of this latter site yields hyper-active condensin that efficiently shortens chromosomes even in the total absence of condensin II.

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Haarhuis et al., Cell, 2017

Loop enlargement by cohesin

The cohesin complex shapes the 3D genome by looping together regulatory elements along chromosomes. We find that chromatin loop size can be increased, and that the duration with which cohesin embraces DNA determines the degree to which loops are enlarged. We conclude that the balanced activity of SCC2/NIPBL-dependent loop extension, and WAPL-mediated DNA release, allows cohesin to correctly structure chromosomes.

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Elbatsh et al., Mol Cell, 2016

How does cohesin release DNA?

Cohesin complexes by default undergo a continuous cycle of DNA entrapment and release. We uncover a functional asymmetry within the heart of cohesin's ABC-like ATPase machinery. Both ATPase sites contribute to DNA loading, whereas DNA release is controlled specifically by one site. We propose that Smc3 acetylation locks cohesin rings around sister DNAs by counteracting an activity associated with this release ATPase site.

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Haarhuis et al., Curr Biol, 2013

Why chromosomes are X-shaped

The classical X-shape of human chromosomes is the consequence of two distinct waves of cohesin removal. First cohesin is removed from arms, and only then from centromeres. We find that this two-step removal process allows the disentanglement of sister chromatids, and the correction of erroneous microtubule-kinetochore attachments. The two-step cohesin removal process thus is essential for proper chromosome segregation.

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Rowland et al., Mol Cell, 2009

Building sister chromatid cohesion

The co-entrapment of sister DNAs inside cohesin rings is dependent on the Eco1 acetyltransferase. We find that Eco1 triggers cohesion establishment by acetylating two key lysines in cohesin's Smc3 subunit. This acetylation counteracts an 'anti-establishment' activity associated with Wapl, and domains of Scc3 and Pds5. Smc3 acetylation turns out to stabilize cohesive cohesin by counteracting the opening of cohesin rings by Wapl.

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Dekker et al., Science, 2023

Shaping the genome with SMC motors

How do meters of DNA fit into our tiny cells? Benjamin and colleagues propose a mechanism for how SMC molecular motors fold our DNA into loops. "Such a mechanism may shape the DNA of all life on earth.”

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Hoencamp & Rowland, Nature Reviews Mol Cell Biol, 2023

Genome control by SMC complexes

SMC complexes are molecular machines that can connect DNA elements in cis, walk along DNA, build and processively enlarge DNA loops and connect DNA molecules in trans to hold together the sister chromatids. These DNA-shaping abilities place SMC complexes at the heart of many DNA-based processes in interphase and mitosis.

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Oldenkamp & Rowland, Mol Cell, 2022

A walk through the SMC cycle

The SMC family of protein complexes is conserved across all domains of life. In this perspective article, we discuss the repertoire of conformational states that SMC complexes can adopt, and consider the potential mechanisms through which SMC complexes could shape DNAs.

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van Ruiten & Rowland, Current Opinions, 2022

A grand pas-de-deux of cohesin & CTCF

How CTCF controls cohesin has long been a mystery. Recent work shows that CTCF dictates chromatin looping via a direct interaction of its N-terminus with cohesin. In this review, we discuss recent insights and consider how cohesin and CTCF together may orchestrate the folding of the genome into chromosomal loops.

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Sedeño Cacciatore & Rowland, Current Opinions, 2019

Turning heads and bending elbows

From the dynamic interphase genome to compacted mitotic chromosomes, DNA is organized by the SMC complexes cohesin and condensin. The picture emerges that these complexes structure the genome through a shared basic principle. We discuss the latest insights into how ATPase-driven conformational changes within these complexes may enlarge loops.

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van Ruiten & Rowland, Trends in Genetics, 2018

How do SMC complexes build loops?

What drives the formation of chromatin loops has been a long-standing question in chromosome biology. SMC complexes, conserved from bacteria to humans, turn out to be key to this process. These complexes structure chromosomes to enable mitosis and long-range gene regulation. Read our review on the wonderful world of SMC complexes.

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Haarhuis et al., Dev Cell, 2014

The logic of X-shaped chromosomes

The X shape of chromosomes is one of the iconic images in biology. Cohesin in fact connects the sisters along their entire length until early mitosis. Then, cohesin's antagonist Wapl allows the separation of chromosome arms, resulting in the X shape of mitotic chromosomes. Check out our review on cohesin, its regulation, and the logic of X-shaped chromosomes.

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Our Discoveries

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