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Scaffidi P.,The Francis Crick Institute | Scaffidi P.,University College London
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2016

Chromatin-related proteins have emerged as important players in the initiation and maintenance of several types of cancer. In addition to the established role of histone-modifying enzymes and chromatin remodelers in promoting and sustaining malignant phenotypes, recent findings suggest that the basic components of chromatin, the histone proteins, also suffer severe alterations in cancer and may contribute to the disease. Histopathological examination of clinical samples, characterization of the mutational landscape of various types of cancer and functional studies in cancer cell lines have highlighted the linker histone H1 both as a potential biomarker and a driver in cancer. This review summarizes H1 abnormalities in cancer identified by various approaches and critically discusses functional implications of such alterations, as well as potential mechanisms through which they may contribute to the disease. This article is part of a Special Issue entitled: Histone H1, edited by Dr. Albert Jordan. © 2015 Elsevier B.V. Source

Uhlmann F.,The Francis Crick Institute
Nature Reviews Molecular Cell Biology | Year: 2016

SMC (structural maintenance of chromosomes) complexes — which include condensin, cohesin and the SMC5–SMC6 complex — are major components of chromosomes in all living organisms, from bacteria to humans. These ring-shaped protein machines, which are powered by ATP hydrolysis, topologically encircle DNA. With their ability to hold more than one strand of DNA together, SMC complexes control a plethora of chromosomal activities. Notable among these are chromosome condensation and sister chromatid cohesion. Moreover, SMC complexes have an important role in DNA repair. Recent mechanistic insight into the function and regulation of these universal chromosomal machines enables us to propose molecular models of chromosome structure, dynamics and function, illuminating one of the fundamental entities in biology. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source

Kelly F.D.,Rockefeller University | Nurse P.,The Francis Crick Institute
PLoS ONE | Year: 2011

Eukaryotic cells often form polarized growth zones in response to internal or external cues. To understand the establishment of growth zones with specific dimensions we used fission yeast, which grows as a rod-shaped cell of near-constant width from growth zones located at the cell tips. Removing the cell wall creates a round spheroplast with a disorganized cytoskeleton and depolarized growth proteins. As spheroplasts recover, new growth zones form that resemble normal growing cell tips in shape and width, and polarized growth resumes. Regulators of the GTPase Cdc42, which control width in exponentially growing cells, also control spheroplast growth zone width. During recovery the Cdc42 scaffold Scd2 forms a polarized patch in the rounded spheroplast, demonstrating that a growth zone protein can organize independent of cell shape. Rga4, a Cdc42 GTPase activating protein (GAP) that is excluded from cell tips, is initially distributed throughout the spheroplast membrane, but is excluded from the growth zone after a stable patch of Scd2 forms. These results provide evidence that growth zones with normal width and protein localization can form de novo through sequential organization of cellular domains, and that the size of these growth zones is genetically controlled, independent of preexisting cell shape. © 2011 Kelly, Nurse. Source

Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 314.75K | Year: 2016

This research project is aimed at understanding the mechanism of sex determination in the chicken i.e. the series of molecular events that determine whether the embryonic gonad develops as a testis or as an ovary. It is widely recognized that such primary sex determining mechanisms evolve rapidly, as exemplified by the marked differences between mammals and other vertebrates. Gonadogenesis in mammals is envisaged as a linear process that is dependent on a switch mechanism based on the Y-chromosome gene Sry. If Sry is expressed appropriately, then the developing gonad becomes a testis: without Sry the gonad becomes an ovary. With only limited exceptions, extensive studies to identify similar master switch genes in other vertebrate species have been unsuccessful. In our studies, we have demonstrated that chicken cells acquire an inherent sex identity at fertilisation or shortly thereafter and believe that this is key to avian sex determination; i.e. the testis forms because the genital ridge is composed of male cells or the ovary forms because the genital ridge is composed of female cells. This suggests that, in birds, rather than gonadal sex determination depending on a sex-specific switch mechanism, testis and ovary differentiation represent two separate pathways. It was widely accepted that once gonadal fate had been determined, it was permanent, but some surprising recent findings suggest that this is not the case. In fact, the adult mammalian gonad displays a great degree of plasticity and testicular and ovarian identity has to be maintained throughout life. It appears that this maintenance depends on the expression of two genes, DMRT1 in males or FOXL2 in female. Dmrt1 has also been shown to be necessary for the proper development and survival of male germ cells. Dmrt1 and Foxl2 are not thought to be important for primary sex determination events in the mouse embryo, but they have been shown to play key roles in gonadogenesis in several vertebrate species including the chick and some mammals. It may be that the requirement for DMRT1 and FOXL2 to maintain adult mammalian gonads represent an evolutionary residue of their major roles in primary sex determining mechanisms in lower vertebrates, where plasticity is often evident during embryonic stages. It is also possible that, unlike the mouse, a number of mammalian species retain elements or this earlier primary sex determining system. We will investigate the possibility that Dmrt1 and Foxl2 balance of expression determines the sexual fate of the embryonic gonads in birds. To do this, we will use cutting edge methods of genetic manipulation to delete copies of Dmrt1 and Foxl2 from the genome of chicken germ cells (PGC) and use these germ cells to derive birds with these genetic mutations. We will assess the effects of these deletions on PGC growth in culture and on germ cell development after injection of PGCs into embryos. Injected embryos will be hatched and raised to sexual maturity and crossed with wild-type birds: by selective crossing we can generate birds with either one or no copies of Dmrt1 or Foxl2. We will compare the development of the gonads and germ cells in these manipulated birds with that in wild-type male and female birds, and so determine the effect of Dmrt1 and Foxl2 on primary sex determination and germ cell development in birds. We will also carry out a series of molecular analyses to determine the networks of genes regulated by Dmrt1 and Foxl2, and identify the genes affected by manipulating the expression levels/ balance of these transcription factors.

Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 318.76K | Year: 2016

Understanding the biology of the metabolic network is key for biotechnology, where single cellular organisms such as budding yeast are used to produce proteins, vaccines or antibiotics. A metabolic network formed from similar reactions operates in mammalian cells, and changes during a lifetime being considered a main driver of ageing and age-associated disorders. Here we are applying for an industrial/academic partnership that will bring a new level into the understanding of this largest of all cellular systems, by creating an enzyme-centric quantitative map that spans the yeast genome. With our industrial partner Sciex, we establish a unique technological platform that can quantify 80% of metabolic enzymes in less than 30 minutes. We will apply this platform to measure enzymes in a collection of ~4800 yeast strains, each of which is lacking one gene at a time. In this way, we connect the majority of all genes in the genome with the metabolites and metabolic enzymes they affect. This map will be the most comprehensive investigation into a eukaryotic proteome conducted so far, and address both already known genes, and genes for which there is only little or no functional information so far available. We will learn about the function of new genes in two ways, first by studying their direct impact on the proteome and metabolism, and by associating them with the already known genes on the basis of their proteomic footprint. For these reasons, the project is of unique value to the mass spec manufacturing industry, that seeks possibilities to bring proteomic technology into environmental analytics, to biotechnology, that lacks information about metabolic networks so that they can exploit it for improving production cycles, and for basic science, that will gain unique insights into the function of novel genes and can use it to develop new strategies for addressing ageing-associated disease.

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