Polymer Modeling Predicts Chromosome Reorganization in Senescence

Chiang, Michael; Michieletto, Davide; Brackley, Chris A.; Rattanavirotkul, Nattaphong; Mohammed, Hisham; Marenduzzo, Davide; Chandra, Tamir

doi:10.1016/j.celrep.2019.08.045

Cited by 63 publications

(98 citation statements)

References 77 publications

(158 reference statements)

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“…SAFH contain heterochromatic late-replicating regions with high A-T content that correspond to identified LADs (Chandra et al, 2015), consistent with the observed decrease in Lamin B1 levels in senescent cells (Shah et al, 2013). Moreover, a polymer model similar to the one used by Falk et al (2019) predicts that SAHF establishment requires a high affinity among heterochromatic regions and a weak association between the nuclear lamina and chromatin (Chiang et al, 2019). Therefore SAFH form by heterochromatin-driven interactions between LADs detached from the nuclear periphery during senescence.…”

Section: Senescence-associated Heterochromatin Focisupporting

confidence: 69%

Heterochromatin as an Important Driver of Genome Organization

Penagos-Puig

Furlan-Magaril

2020

Front. Cell Dev. Biol.

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Heterochromatin is a constituent of eukaryotic genomes with functions spanning from gene expression silencing to constraining DNA replication and repair. Inside the nucleus, heterochromatin segregates spatially from euchromatin and is localized preferentially toward the nuclear periphery and surrounding the nucleolus. Despite being an abundant nuclear compartment, little is known about how heterochromatin regulates and participates in the mechanisms driving genome organization. Here, we review pioneer and recent evidence that explores the functional role of heterochromatin in the formation of distinct chromatin compartments and how failure of the molecular mechanisms forming heterochromatin leads to disarray of genome conformation and disease.

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Section: Senescence-associated Heterochromatin Focisupporting

confidence: 69%

Heterochromatin as an Important Driver of Genome Organization

Penagos-Puig

Furlan-Magaril

2020

Front. Cell Dev. Biol.

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“…The former retains only the repulsive part of the potential while the latter choice includes a spherical shell in which the spherical body is attractive to DNA beads with a binding energy that we set to 0.7 . These choices are wellestablished in the field for modelling DNA and chromatin binding proteins such as transcription factors (18,36).…”

Section: Modelling Of Dna and Cohesinmentioning

confidence: 99%

Phase separation induced by cohesin SMC protein complexes

Ryu

Bouchoux

Liu

et al. 2020

Preprint

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Cohesin is a key protein complex that organizes the spatial structure of chromosomes during interphase. Here, we show that yeast cohesin shows pronounced clustering on DNA in an ATPindependent manner, exhibiting all the hallmarks of phase separation. In vitro visualization of cohesin on DNA shows DNA-cohesin clusters that exhibit liquid-like behavior. This includes mutual fusion and reversible dissociation upon depleting the cohesin concentration, increasing the ionic strength, or adding 1,6-hexanediol, conditions that disrupt weak interactions. We discuss how bridging-induced phase separation can explain the DNA-cohesin clustering through DNA-cohesin-DNA bridges. We confirm that, in vivo, a fraction of cohesin associates with chromatin in yeast cells in a manner consistent with phase separation. Our findings establish that SMC proteins can exhibit phase separation, which has potential to clarify previously unexplained aspects of in vivo SMC behavior and constitute an additional principle by which SMC complexes impact genome organization. One sentence summary:Yeast cohesin complex is observed to phase separate with DNA into liquid droplets, which it accomplishes by ATP-independent DNA bridging.Members of the structural maintenance of chromosome (SMC) protein family such as condensin, cohesin, and the Smc5/6 complex are key proteins for the spatial and temporal organization of chromosomes (1)(2)(3)(4). Recent in vitro experiments visualized real-time DNA loop extrusion mediated by condensin and cohesin (5-7). While loop extrusion by SMC proteins constitutes a fundamental building block in the organization of chromosomes, other factors may also contribute. In the last decade, it has become abundantly clear that phase separation plays a role in many processes in biological cells (8), including chromosome organization (9, 10). Thus far, SMC proteins have not been implied in phase separation. While ATP-independent clustering of DNA and SMC proteins has been reported (11)(12)(13)(14), such observations were attributed to imperfect protein purification or non-physiological buffer conditions. For example, Davidson et al. (7) reported in vitro DNA loop extrusion by the human cohesin complex when the complex concentration was limited to very low values (<0.8 nM, i.e., much lower that physiological concentrations of ~333 nM (15,16), and mentioned that the cohesin complexes were prone to aggregation at higher concentrations. Such findings raise the question whether such aggregate formation may be intrinsic and may have a physiological meaning.Here we report that interactions between the yeast cohesin SMC complex and DNA lead to pronounced phase separation. This clustering behavior is ATP independent but depends on DNA length. We find that single cohesin complexes are able to bridge distant points along DNA that act as nucleation points for recruiting further cohesin complexes -a behavior indicating bridging-induced phase separation (BIPS) (17,18), also known as polymer-polymer phase separation (PPPS) (19), a type of phase co...

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“…Block co-polymer models further show that this process is favored by homotypic interactions between heterochromatic domains [ 31 ]; interestingly, models of inverted nuclei recapitulate chromatin inversions and the loss of peripheral heterochromatin [ 31 ]. Polymer models can also provide a physical explanation for phase transitions promoting contact or dissociation of chromatin with/from the nuclear lamina [ 32 ]. They also infer that regions of euchromatin can be dragged alongside heterochromatin and be co-adsorbed onto the interacting surface [ 32 ]; this could provide one explanation for the heterogeneity in the sequence and chromatin composition of LADs [ 20 ].…”

Section: Introductionmentioning

confidence: 99%