Shaping the genome

Chromosome organization

by cohesin & condensin

 

 

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Research

If you are not a scientist, then read this article in which Benjamin explains our research, and also watch our lecture for the non-specialist further down this page.

For our discoveries, check out this link.

Shaping the genome in interphase and mitosis

Cells are only a few micrometers in size, yet each cell harbours our entire genome. These meters of DNA need to be organized in 3D to control many important cellular events. Key to this organization are two highly conserved protein complexes known as cohesin and condensin. Both cohesin and condensin are so-called SMC complexes that by building DNA loops, and by holding together DNA elements, can provide structure to chromosomes. Broadly speaking, our research can be divided over three themes:

1) Building chromatin loops in interphase

Cohesin plays a major role in the 3D organization of the interphase genome as it loops together regulatory elements along chromosomes. We recently found that such DNA loops can be increased in size, and that the duration with which cohesin entraps DNA determines the degree to which loops are enlarged. Cohesin has a dynamic mode of DNA binding that involves a cycle of DNA entrapment and WAPL-mediated DNA release. This apparently allows for a constant cycle of the formation, enlargement, loss, and re-formation of loops that keeps the interphase genome dynamic. See e.g. Haarhuis et al. and Li et al. for our research on interphase genome organization by cohesin.

2) Holding together the sister chromatids

In addition to its role in building loops, cohesin also holds together the sister chromatids of each chromosome. From DNA replication onwards, cohesin co-entraps the sister DNAs inside its ring-shaped structure, and cohesin holds together these sisters until mitosis. Cohesin then resists the pulling forces of microtubules until all chromosomes are correctly aligned at the metaphase plate. The abrupt cleavage of cohesin rings then triggers the synchronous segregation of sister chromatids to the opposite poles of the cell. See e.g. Elbatsh et al. and Haarhuis et al. for our papers on sister chromatid cohesion.

3) Mitotic chromosome condensation

As cells enter mitosis, condensin complexes convert the genome into compact and rigid chromosomes. Condensin drives chromosome condensation through the formation of loops along the DNA. This vital process shortens chromosomes to allow the splitting in half of the cell during cytokinesis without DNA getting caught in the middle. Cohesin and condensin therefore both have an essential role in mitosis that ensures that each of the daughter cells receives an equal karyotype during cell division. See e.g. Elbatsh et al. for our work on condensin.

Research questions

Key questions to us are: How do cohesin and condensin form DNA loops and shape the genome in 3D? How do these complexes entrap and release DNA? How does cohesin stably lock together the sister chromatids? How does condensin drive mitotic chromosome condensation? And how does loop formation by these complexes affect nuclear organization and gene expression? These are the kind of questions that keep us awake at night and drive our research. We are addressing such questions using a multi-disciplinary approach that involves genetics, genomics, biochemistry and imaging.

For our research highlights, check out our selected publications.

Chromosomes for dummies

If you are not a scientist, but would like to learn about our research, then watch Benjamin explain cell division and chromosomes (in Dutch):

Positions available

We are recruiting. If you are interested in joining our lab, please send an enquiring email including your CV and motivation to Benjamin (b.rowland AT nki.nl).

Research in our lab is supported by the European Research Council (ERC), the Dutch Cancer Society (KWF), and the Dutch Research Council (NWO).


Research highlights

Genome folding by cohesin & CTCF

Cohesin catalyzes folding of 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 is essential for CTCF-anchored loops. This interaction stabilizes cohesin on chromatin, and contributes to the positioning of cohesin at CTCF binding sites. We propose that CTCF enables chromatin loop formation by protecting cohesin against loop release. Our results provide fundamental insights into the molecular mechanism that allows dynamic chromatin folding by cohesin and CTCF.

Read this paper and our press release.

Condensin exibits self-restraint

Chromosome condensation by condensin complexes is essential for faithful chromosome segregation. 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. Condensin II turns out to be specifically required for the decatenation of sister chromatids, and for the formation of a straight chromosomal axis.

Read this paper and its commentary in Science.

 

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. Our data support the model that cohesin structures chromosomes through the processive enlargement of loops, and that this counteracts nuclear compartmentalization. We conclude that the balanced activity of SCC2/NIPBL-dependent loop extension, and WAPL-mediated DNA release, allows cohesin to correctly structure chromosomes.

Read this paper and our press release.

How does cohesin release DNA?

Cohesin complexes by default undergo a continous cycle of DNA entrapment and release. Smc3 acetylation allows stable sister DNA entrapment as it prevents DNA release. We uncover a functional asymmetry within the heart of cohesin's ABC-like ATPase machinery, and find that both ATPase sites contribute to DNA loading, whereas DNA release is controlled specifically by one site. We find that this mechanism is conserved from yeast to humans. We propose that Smc3 acetylation locks cohesin rings around the sister DNAs by counteracting an activity associated with one of cohesin's two ATPase sites.

Read this paper, its commentary, and view our cover.

 

Why chromosomes are X-shaped

The classical X-shape of human chromosomes is the consequence of two distinct waves of cohesin removal. The first wave specifically drives cohesin from chromosome arms, while the second removes centromeric cohesin. We find that this two-step removal process is important to allow the disentanglement or 'decatenation' of sister chromatids. In addition it allows the focusing of Aurora B at centromeres, which in turn is crucial to correct erroneous microtubule-kinetochore attachments. As such, the two-step cohesin removal process is essential for proper chromosome segregation.

Read this paper and its commentary.

Building sister chromatid cohesion

The establishment of cohesion is a delicate affair that involves the co-entrapment of sister DNAs inside cohesin rings in the wake of replication forks. This process 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 that is associated with Wapl and certain domains of Scc3 and Pds5. Our current understanding is that Smc3 acetylation stabilizes cohesive cohesin by counteracting the opening of cohesin rings by Wapl.

Read this paper and its commentary.

Our reviews

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.

Read this paper

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.

Read this paper

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.

Read this paper

 


News

Anchoring loops by CTCF

We published our paper in Nature on how the interaction between CTCF and cohesin folds the genome into loops.

Read the press release and our paper.

KWF grant awarded to Benjamin

Benjamin was awarded a grant from the KWF to investigate the role of a conserved domain of cohesin in genome regulation.

Check out the awarded grants.

KWF grant to Judith and Benjamin

We were awarded a grant from the KWF to study the role of SWI/SNF chromatin remodellers in cohesin regulation.

Read about this grant (in Dutch).

 

Claire receives BIF fellowship

Claire was awarded a competitive fellowship from the Boehringer Ingelheim Fonds that will fund her for two years. We are proud, also because Marjon received this same fellowship 18 months ago.

Read the interview with Claire.

Chromosomes for dummies

Benjamin gave a lecture for the layman on cell division and chromosomes. If you are not a scientist, but do want to understand our research, then watch this lecture on YouTube.

Watch Benjamin's lecture (in Dutch).

ERC Consolidator Grant awarded to Benjamin

Benjamin was awarded a prestigious ERC Consolidator Grant to investigate the mechanism by which cohesin structures interphase chromosomes.

Read the interview with Benjamin.

 

Benjamin in 'de Volkskrant'

Researchers from Delft and Heidelberg catch condensin in the act. They reveal that condensin shapes DNA by extruding loops. Benjamin comments on this important work in a leading national newspaper.

Read this article (in Dutch).

Judith wins the AVL Award

Judith has won the Antoni van Leeuwenhoek Award for her fundamental discoveries in chromosome biology. This coveted prize is awarded to the most talented postdoc or PhD student of the year.

Read the interview with Judith.

Building loops by cohesin

We published our paper in Cell on how cohesin builds loops. We tested a famous model proposed back in 2001. The mechanism that we describe is likely to shape the genomes of all life on earth.

Read the press release and our paper.

Meet the crew

 

Judith

Postdoc

 

Marjon

PhD Student

 

Alberto

PhD Student

 

Benjamin

Principal Investigator

 

Claire

PhD Student

 

Roel

PhD Student

 

Ángela

PhD Student

 

Laureen

Technician

 

Giorgio

Postdoc

 

Démi

Technician

 

Virginie

Postdoc

 

Kyah

Student

 

 


Contact

 

 

Are you interested in joining our team?

Feel free to send an equiring email to:

b.rowland AT nki.nl

Benjamin Rowland
The Netherlands Cancer Institute
Division of Gene Regulation
Plesmanlaan 121
1066 CX Amsterdam
The Netherlands