Uddipta Biswas (Jessberger, TUD)-- «Dissecting the roles
of cohesin complexes in murine spermatocytes» (2014)
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.
Gamze Gunal (Jessberger, TUD)-- «Stage - specific binding profile of
cohesin in resting and switch - activated B lymphocytes» (2013)
«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.
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.
They found that a large protein complex
called cohesin is positioned as a ring around the two DNA strands that are formed when a cell divides, marking virtually all the places on the DNA where transcription factors were bound.
In previous studies, researchers proved in mice that genes of the
meiotic cohesin complex produce various degrees of infertility in mice.
His research currently focuses on determining the mechanisms and consequences of
cohesin gene inactivation in human cancer.
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.
Our results have revealed that although condensin and
cohesin bind to the same gene loci, they direct different association networks (Figure).
Decreased cohesin in the brain alters gene expression leading to the disruption of neuronal network formation
Currently, extensive research is conducted to better understand the role of certain
cohesin mutations in cancers such as glioblastoma, or Ewing's sarcoma.
Cohesin forms small topological chromatin domains of approximately 100 kb, while condensin organizes 300 kb — 1 Mb domains.
Cohesin controls gene expression and chromatin structure, as well as enabling chromosomes to separate correctly immediately prior to cell division.
«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.
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.
Meiotic
Cohesin SMC1β Provides Prophase I Centromeric Cohesion and Is Required for Multiple Synapsis - Associated Functions.
Cornelia Blei (Jessberger, TUD)-- «The role of
cohesin SMC1ß and its chromosome association in murine meiosis» (2012)
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.
Yan J, Enge M, Whitington T, Dave K, Liu J, Sur I, Schmierer B, Jolma A, Kivioja T, Taipale M, Taipale J. Transcription Factor Binding in Human Cells Occurs in Dense Clusters Formed
around Cohesin Anchor Sites.
There is good evidence that
initial cohesin loading is already topological (meaning, the ring closes around the single chromatid).
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».
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.
When the second sister chromatid is synthesized in S phase,
cohesin establishes sister chromatid cohesion in a co-replicative manner (only after you have the second sister chromatid, you can actually start talking about «cohesion»).
Cohesin mediates local contacts, i.e. between loci positioned within 100 kb (red), whereas condensin drives longer - range contacts (blue).
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.
Soon
after cohesin was described as this guardian of sister chromatid cohesion, it also became clear that there is just more to it.
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.
Because of its pleiotropic functions, defects in
human cohesin biology can cause a number of clinically relevant issues.
How condensin and
cohesin govern the 3D structure of the eukaryotic genome is an exciting research area.
Meiotic
cohesin STAG3 is required for chromosome axis formation and sister chromatid cohesion.
The main focus of our research is to understand the regulation of gene expression
by cohesin and related proteins, which are also required for sister chromatid cohesion during mitosis (see «Background»).
In a recent issue of Current Biology, Lampson and Schultz concluded that the increase in chromosomal disorders experienced by older women is largely related to a decrease in
cohesin proteins, which diminish as a part of the aging process.
This gluing occurs by the action of proteins
called cohesins that are usually enriched at the compact «connection region.»
Today we have good evidence showing that
cohesin binds to chromosomal insulator elements that are usually associated with the CTCF (CCCTC - binding factor) transcriptional regulator.
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.
«This also raises the possibility that mild mutations in
cohesin genes may be the cause of some fraction of congenital heart defects in the general population,» she says.
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.
Mutations in the genes encoding proteins that regulate
cohesin and cohesin protein itself cause the developmental disorder Cornelia de Lange syndrome (CdLS).
Research coordinated by Osaka University has now shown that the nuclear protein complex
cohesin must be expressed at sufficient levels in the early mouse brain to control gene regulation and allow development of healthy neuronal networks and behavioral characteristics.
«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.»
With this in mind, the researchers switched off expression of the mouse Smc3 gene, which encodes part of
the cohesin complex, in particular cell types to assess its function.
«Our findings suggest that heart development is exquisitely sensitive to the available amount of Rad21 and
cohesin — it can be compromised even when there is sufficient cohesin present to support relatively normal growth.
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.
«Mice with reduced expression of
cohesin had abnormalities in the development of nerve cell branches and junctions (synapses) in the cerebral cortex, the gray matter of the brain that is responsible for consciousness and memory,» study first author Yuki Fujita says.
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.
Cohesin would function as an indicator of which DNA sequences might contain disease - causing mutations.
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.
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.