This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of 'tumour progenitor genes'. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: 'epigenetic mediators', corresponding to the tumour progenitor genes suggested earlier; 'epigenetic modifiers' of the mediators, which are frequently mutated in cancer; and 'epigenetic modulators' upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.

/pdf/epigenetic-modulators-modifiers-and-mediators-in-cancer-4aieifzu1c.pdf

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

Kinetochores are large protein assemblies that connect chromosomes to microtubules of the mitotic and meiotic spindles in order to distribute the replicated genome from a mother cell to its daughters. Kinetochores also control feedback mechanisms responsible for the correction of incorrect microtubule attachments, and for the coordination of chromosome attachment with cell cycle progression. Finally, kinetochores contribute to their own preservation, across generations, at the specific chromosomal loci devoted to host them, the centromeres. They achieve this in most species by exploiting an epigenetic, DNA-sequence-independent mechanism; notable exceptions are budding yeasts where a specific sequence is associated with centromere function. In the last 15 years, extensive progress in the elucidation of the composition of the kinetochore and the identification of various physical and functional modules within its substructure has led to a much deeper molecular understanding of kinetochore organization and the origins of its functional output. Here, we provide a broad summary of this progress, focusing primarily on kinetochores of humans and budding yeast, while highlighting work from other models, and present important unresolved questions for future studies.

A Molecular View of Kinetochore Assembly and Function.

The centromere, responsible for chromosome segregation during mitosis, is epigenetically defined by CENP-A containing chromatin. The amount of centromeric CENP-A has direct implications for both the architecture and epigenetic inheritance of centromeres. Using complementary strategies, we determined that typical human centromeres contain ∼400 molecules of CENP-A, which is controlled by a mass-action mechanism. This number, despite representing only ∼4% of all centromeric nucleosomes, forms a ∼50-fold enrichment to the overall genome. In addition, although pre-assembled CENP-A is randomly segregated during cell division, this amount of CENP-A is sufficient to prevent stochastic loss of centromere function and identity. Finally, we produced a statistical map of CENP-A occupancy at a human neocentromere and identified nucleosome positions that feature CENP-A in a majority of cells. In summary, we present a quantitative view of the centromere that provides a mechanistic framework for both robust epigenetic inheritance of centromeres and the paucity of neocentromere formation.DOI: http://dx.doi.org/10.7554/eLife.02137.001.

/pdf/the-quantitative-architecture-of-centromeric-chromatin-5e18b84mm9.pdf

The quantitative architecture of centromeric chromatin

The propagation of all organisms depends on the accurate and orderly segregation of chromosomes in mitosis and meiosis. Budding yeast has long served as an outstanding model organism to identify the components and underlying mechanisms that regulate chromosome segregation. This review focuses on the kinetochore, the macromolecular protein complex that assembles on centromeric chromatin and maintains persistent load-bearing attachments to the dynamic tips of spindle microtubules. The kinetochore also serves as a regulatory hub for the spindle checkpoint, ensuring that cell cycle progression is coupled to the achievement of proper microtubule–kinetochore attachments. Progress in understanding the composition and overall architecture of the kinetochore, as well as its properties in making and regulating microtubule attachments and the spindle checkpoint, is discussed.

https://www.genetics.org/content/genetics/194/4/817.full.pdf

The composition, functions, and regulation of the budding yeast kinetochore.

We review the phenomenology and theory of bulk observables in ultra-relativistic heavy-ion collisions, focusing on recent developments involving event-by-event fluctuations in the initial stages of a heavy-ion collision, and how they manifest in observed correlations. We first define the relevant observables and show how each measurement is related to underlying theoretical quantities. Then we review the prevailing picture of the various stages of a collision, including the state-of-the-art modeling of the initial stages of a collision and subsequent hydrodynamic evolution, as well as hadronic scattering and freeze-out in the later stages. We then discuss the recent results that have shaped our current understanding and identify the challenges that remain. Finally, we point out open issues and the potential for progress in the field.

http://iopscience.iop.org/article/10.1088/0954-3899/41/6/063102/pdf

Initial state fluctuations and final state correlations in relativistic heavy-ion collisions

The mechanisms by which sister chromatids maintain biorientation on the metaphase spindle are critical to the fidelity of chromosome segregation. Active force interplay exists between predominantly extensional microtubule-based spindle forces and restoring forces from chromatin. These forces regulate tension at the kinetochore that silences the spindle assembly checkpoint to ensure faithful chromosome segregation. Depletion of pericentric cohesin or condensin has been shown to increase the mean and variance of spindle length, which have been attributed to a softening of the linear chromatin spring. Models of the spindle apparatus with linear chromatin springs that match spindle dynamics fail to predict the behavior of pericentromeric chromatin in wild-type and mutant spindles. We demonstrate that a nonlinear spring with a threshold extension to switch between spring states predicts asymmetric chromatin stretching observed in vivo. The addition of cross-links between adjacent springs recapitulates coordination between pericentromeres of neighboring chromosomes.

/pdf/pericentric-chromatin-loops-function-as-a-nonlinear-spring-3heivvvs78.pdf

Pericentric chromatin loops function as a nonlinear spring in mitotic force balance

A 3D Map of the Yeast Kinetochore Reveals the Presence of Core and Accessory Centromere-Specific Histone

We present a novel shadow map parameterization to reduce perspective aliasing artifacts for both point and directional light sources. We derive the aliasing error equations for both types of light sources in general position. Using these equations we compute tight bounds on the aliasing error. From these bounds we derive our shadow map parameterization, which is a simple combination of a perspective projection with a logarithmic transformation. We formulate several types of logarithmic perspective shadow maps (LogPSMs) by replacing the parameterization of existing algorithms with our own. We perform an extensive error analysis for both LogPSMs and existing algorithms. This analysis is a major contribution of this paper and is useful for gaining insight into existing techniques. We show that compared with competing algorithms, LogPSMs can produce significantly less aliasing error. Equivalently, for the same error as competing algorithms, LogPSMs can produce significant savings in both storage and bandwidth. We demonstrate the benefit of LogPSMs for several models of varying complexity.

/pdf/logarithmic-perspective-shadow-maps-14yvc2150a.pdf

Logarithmic perspective shadow maps

In mitosis, the pericentromere is organized into a spring composed of cohesin, condensin, and a rosette of intramolecular chromatin loops. Cohesin and condensin are en- riched in the pericentromere, with spatially distinct patterns of localization. Using model convolution of computer simulations, we deduce the mechanistic consequences of their spa- tial segregation. Condensin lies proximal to the spindle axis, whereas cohesin is radially dis- placed from condensin and the interpolar microtubules. The histone deacetylase Sir2 is re- sponsible for the axial position of condensin, while the radial displacement of chromatin loops dictates the position of cohesin. The heterogeneity in distribution of condensin is most accurately modeled by clusters along the spindle axis. In contrast, cohesin is evenly distrib- uted (barrel of 500-nm width × 550-nm length). Models of cohesin gradients that decay from the centromere or sister cohesin axis, as previously suggested, do not match experimental images. The fine structures of cohesin and condensin deduced with subpixel localization ac - curacy reveal critical features of how these complexes mold pericentric chromatin into a functional spring.

The spatial segregation of pericentric cohesin and condensin in the mitotic spindle

https://www.physics.ncsu.edu/wang/pdfs/2011%20High%20accurary%20Fronczek%20FIONA_AFM.pdf

Cory Quammen

Papers

Pericentric chromatin loops function as a nonlinear spring in mitotic force balance

A 3D Map of the Yeast Kinetochore Reveals the Presence of Core and Accessory Centromere-Specific Histone

Logarithmic perspective shadow maps

The spatial segregation of pericentric cohesin and condensin in the mitotic spindle

High accuracy FIONA–AFM hybrid imaging