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NUCLEAR ARCHITECTURE

FÁTIMA MANZANO NÚÑEZ. NUCLEAR ARCHITECTURE. Sequencing projects. E lucidation of the cellular organization of genomes and its impact on genome regulation and activity. Next step. Q uestions. How is the genome organized in 3D space?

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NUCLEAR ARCHITECTURE

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  1. FÁTIMA MANZANO NÚÑEZ NUCLEAR ARCHITECTURE

  2. Sequencing projects Elucidation of the cellular organization of genomes and its impact on genome regulation and activity Next step

  3. Questions • How is the genome organized in 3D space? • What are the fundamental principles of organization? • What are the molecular mechanisms that give rise to the organization patterns? • What are the physiological consequences of spatial genome organization?

  4. Chromatin organization Loops LADs Fig.1 T. Cremer and C. Cremer. Nature reviews . Vo. 2. 2001

  5. LADs LADslamina associated domains Low gene expression levels Nearly 40% of human genome consist on LADs Only structural properties? Lars Guelen et al. Nature. Vo. 453. 2008.

  6. LADs DamID technique Study the association of chromatin to any protein Dam (DNA adenine methyltansferase) + Protein Methylated regions are amplified (PCR) and analyzed by high-throughput techniques (microarrays or sequencing). Alejandro Rodriguez et al. Biochemical Society Transactions . Vo. 41, p. 6, 2013.

  7. LADs Study LADs by DamID Interaction map Dam -Lamin B1 a)High levels of LADs alternate with low levels. Sharp transitions. b) and c) LADs vary in size and are frequently 1 megabase (Mb) in size or larger Fig. 1. Lars Guelen et al. Nature. Vo. 453. 2008.

  8. LADs Gene density and expression around LAD borders Fig. 4. Lars Guelen et al. Nature. Vo. 453. 2008.

  9. Loops Loops Structural elements with regulatory functions MHC II cluster Fig.4. Emanuela V. Volpi1 et al. Journal of Cell Science 113, 1565-1576 . 2000. Fig. 2. Tom Misteli. Cell. 128, 787–800, 2007

  10. Chromosome spatial organization Internal vs. peripherial Relative positions Translocations

  11. Internal vs. peripheral Changes in transcriptional activity and gene density Change the position of genes during differentiation Fig.2 Masahiko Kuroda et al. Journal of Cell Science. 117, 5897-5903, 2004.

  12. Relative position Functional consequences of Global chromatin organization Relative position important determinant of function Separate chromosomes into physical interaction corregulating gene loci. Trans-regulation. Separate chromosomes into physical proximity sharing transcription sites. Fig. 3. Tom Misteli. Cell. 128, 787–800, 2007

  13. Translocations Tissue-specific proximity of chromosomes correlates with tissue-specific translocation frequency Tissue specific chromosomes organization Fig.1. Luis A Parada et al. Genome Biology, Vo. 5, 7, R44. 2004 Fig. 3. Tom Misteli. Cell. 128, 787–800, 2007

  14. Conclusions • Such areas that are nearly the lamina have low gene density and transcription. • Loops are structural elements with regulatory functions. • The organization of the genome is related with its regulation. • The organization of the genome depends of the genes that are active or inactive, so also of the kind of cell and its differentiation level. • The organization can follow the internal vs. peripheral pattern or the relative position model. • Translocations have tissue-specific frequency.

  15. Bibliography Alejandro Rodriguez et al. The links between chromatin spatial organization and biological function. Biochemical Society Transactions . Vo. 41, p. 6, 2013. Emanuela V. Volpi1 et al. Large-scale chromatin organization of the major histocompatibility complex and other regions of human chromosome 6 and its response to interferon in interphase nuclei. Journal of Cell Science 113, 1565-1576 . 2000. Lars Guelen et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. Vo. 453. 2008. Luis A Parada et al. Tissue-specific spatial organization of genomes. Genome Biology, Vo. 5, 7, R44. 2004. Masahiko Kuroda et al. Alteration of chromosome positioning during adipocyte differentiation. Journal of Cell Science. 117, 5897-5903, 2004. Shlomit Farkash-Amar et al. Systematic Determination of Replication Activity Type Highlights Interconnections between Replication, Chromatin Structure and Nuclear Localization. Plos one. Vo. 7 , 11, 2012. T. Cremer and C. Cremer. Chromosome territories nuclear architecture and gene regulation in mammalian cells. Nature reviews . Vo. 2. 2001. Tom Misteli. Beyond the Sequence: Cellular Organization of Genome Function. Cell. 128, 787–800, 2007.

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