I also mentioned a protein complex, which is integral for this chromosomal ballet,
the cohesin complex.
Simultaneously,
cohesin's job is to take those newly generated sister chromatids and hold them tightly to the old one.
It was observed quite early that
cohesin can act as an insulation factor, blocking long - range promoter - enhancer association.
Studying
cohesin has, of course, not only academic value.
In the figure: ChIA - PET genomic analyses successfully mapped condensin (left) and
cohesin (right)- mediated gene contacts throughout the fission yeast genome.
These studies demonstrate that the two important protein complexes, condensin and
cohesin, are both essential for the assembly of the functional genome architecture, but their roles in the 3D genome organization (gene contacts and topological domain organization) are significantly different.
Soon after
cohesin was described as this guardian of sister chromatid cohesion, it also became clear that there is just more to it.
Cohesin forms small topological chromatin domains of approximately 100 kb, while condensin organizes 300 kb — 1 Mb domains.
By combining the fission yeast, mouse, and human systems with the latest genomic, genetic, cell biological, and biochemical approaches, we seek to determine how condensin and
cohesin organize the functional 3D genome structures and participate in various biological processes, including transcriptional regulation and chromosomal dynamics, and how they contribute to oncogenic processes.
Meiotic
cohesin STAG3 is required for chromosome axis formation and sister chromatid cohesion.
Currently, extensive research is conducted to better understand the role of certain
cohesin mutations in cancers such as glioblastoma, or Ewing's sarcoma.
After twenty years of research,
the cohesin complex still manages to surprise us regularly, as new functions in new areas of cell cycle regulation come to light.
More specifically, we have been studying the roles of the condensin and
cohesin complexes in 3D genome organization in the fission yeast, mouse and human systems.
Because of its pleiotropic functions, defects in human
cohesin biology can cause a number of clinically relevant issues.
Since actual cohesion defects will cause mitotic failure (which most surely results in cell death), most of
cohesin - associated diseases are believed to be caused by misregulation of the complex's non-canonical functions in replication / transcription.
The last stage in the life of
a cohesin ring is its removal from centromeres, a tightly regulated process, which involves proteolytic cleavage of cohesin's Scc1 / Rad21 subunit (see Figure 2).
It is important to mention
that cohesin also has a very unique role in meiosis where it not only coheses sister chromatids but also chromosomal homologs (the two maternal / paternal versions of a chromosome, each consisting of two sisters, which themselves are cohesed).
However, a small but very important fraction of
cohesin molecules, which is located at the chromosomes» centromere regions, remains protected from this removal mechanism in prophase.
And while this feat should already be enough to warrant devoting a whole blog post to
cohesin, you will shortly realize that this complex also performs a myriad of other functions during the cell cycle, which really makes it «one ring to rule them all».
Our results have revealed that although condensin and
cohesin bind to the same gene loci, they direct different association networks (Figure).
Cohesin has also been shown to have functions in transcriptional regulation.
Our ongoing studies demonstrate that the condensin and
cohesin complexes are key molecular machines that organize the functional 3D genome structures.
Cohesin mediates local contacts, i.e. between loci positioned within 100 kb (red), whereas condensin drives longer - range contacts (blue).
This means that
cohesin has at least the potential to influence a whole bunch of other chromosomal events, like DNA replication, gene expression and DNA topology.
Stage - specific binding profiles of
cohesin in resting and activated B lymphocytes suggest a role for
cohesin in immunoglobulin class switching and maturation.
Cohesin obviously gets its name from the fact that it causes «cohesion» between sister chromatids, which has been first described 20 years ago in budding yeast.
That poses an obvious problem during S phase: While DNA replication machineries («replisomes») zip along the chromosomes trying to faithfully duplicate the entire genome in a matter of just a couple of hours, they encounter — on average — multiple
cohesin rings that are already wrapped around DNA.
According to our current understanding,
cohesin is already loaded onto DNA (along the entire length of the decondensed one - chromatid chromosome) in telophase, i.e. only minutes after chromosome segregation, by opening / closing its Smc1 - Smc3 interaction site (or «entry gate»).
And while we're still far away from completely understanding this complex complex, we already know enough to say that
cohesin really is «one ring to rule them all».
There is good evidence that initial
cohesin loading is already topological (meaning, the ring closes around the single chromatid).
The proteins
Cohesin (blue lines) and CTCF (purple blocks) act as the purse strings of DNA «goody bags» (gray lines).
Interestingly, when mouse neural precursor cells were examined for similar
Cohesin / CTCF - bound loops, not only did the cells have such loops, but they were in similar locations as in the ESC genome.
Hnisz, also a postdoctoral researcher in Young's lab, likens the loops to «goody bags», with
Cohesin and CTCF acting as the purse strings to create a DNA loop that cradles proteins enhancing or repressing gene expression.
In the ESCs they studied, the scientists identified 197
Cohesin / CTCF - flanked loops that contain active genes and enhancers, and 349 loops that contain repressed genes.
«By knowing which of
the Cohesin / CTCF bound sites are coming together in physical proximity, we started to go from a linear view of the genome to sets of looping interactions, which led us to these domains, these super enhancer domains, where gene expression enhancement is contained within the loop,» says Jill Dowen, a postdoctoral researcher in Young's lab.
Cohesin and
cohesin - associated factors and their contribution to genome integrity, chromosome segregation and cell survival
Gamze Gunal (Jessberger, TUD)-- «Stage - specific binding profile of
cohesin in resting and switch - activated B lymphocytes» (2013)
His research currently focuses on determining the mechanisms and consequences of
cohesin gene inactivation in human cancer.
CSIC researcher adds: «We have confirmed that mutation is found in both copies of the gene, one inherited from the father and the other one inherited from the mother, in the four women affected by the disease, causing an absolute absence of STAG3 protein and meiotic
cohesin complex in these women.
In previous studies, researchers proved in mice that genes of the meiotic
cohesin complex produce various degrees of infertility in mice.
Gabriela Cabral, a PhD student in the lab of Alex Dammermann at the Center for Molecular Biology of the University of Vienna, explains: «Many people thought that centrioles are held together by the same glue as chromosomes, a substance called
cohesin, which is destroyed during cell division.
By only analysing DNA sequences that bind to
cohesin, roughly one per cent of the genome, it would allow us to analyse an individual's mutations and make it much easier to conduct studies to identify novel harmful mutations,» Martin Enge concludes.
The discovery that virtually all regulatory DNA sequences bind to
cohesin may also end up having more direct consequences for patients with cancer or hereditary diseases.
Since the two new DNA strands are caught in the ring, only one
cohesin is needed to mark the two, thereby helping the transcription factors to find their original binding region on both DNA strands.
Cohesin encircles the DNA strand as a ring does around a piece of string, and the protein complexes that replicate DNA can pass through the ring without displacing it.
Unless sufficient
cohesin was present in the developing mouse brain, the researchers showed that the regulation of a number of genes was disrupted, leading to neuronal defects and increased anxiety.
«We also found that reduced
cohesin led to changes in the expression of genes involved in nerve cell development and the response to an immune signaling protein,» corresponding author Toshihide Yamashita says.
«Regulator of chromosome structure crucial to healthy brain function and nerve development:
Cohesin protein identified as key to control of chromosome structure underlying nerve cell network formation.»
CdLS is known to result from mutations in subunits or regulators of
cohesin, a group of linked proteins necessary for cell division and other cell processes.
«Now, through our new study, we show that lowering levels of a particular
cohesin protein called Rad21 in embryonic zebrafish produces similar types of heart defects to those found in people with CdLS,» Associate Professor Horsfield says.