NUCLEAR ARCHITECTURE
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NUCLEAR ARCHITECTURE
FÁTIMA MANZANO NÚÑEZ
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Sequencing projects
Elucidation of the cellular organization of genomes and its impact on genome regulation and activity
Next step
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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?
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Chromatin organization
Loops
LADs
Fig.1 T. Cremer and C. Cremer. Nature reviews . Vo. 2. 2001
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LADslamina associated domains
Low gene expression levels
Nearly 40% of human genome consist on LADs
LADs
Only structuralproperties?
Lars Guelen et al. Nature. Vo. 453. 2008.
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DamID technique
Dam (DNA adenine methyltansferase) + Protein
Methylated regions are amplified (PCR) and analyzed by high-throughput techniques
(microarrays or sequencing).
LADs
Study the association of chromatin to any protein
Alejandro Rodriguez et al. Biochemical Society Transactions . Vo. 41, p. 6, 2013.
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Study LADs by DamIDLADs
Dam - Lamin B1
Interaction map
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.
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Gene density and expression around LAD borders
LADs
Fig. 4. Lars Guelen et al. Nature. Vo. 453. 2008.
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LoopsLoops
Structural elements with regulatory functions
Fig. 2. Tom Misteli. Cell. 128, 787–800, 2007
MHC II cluster
Fig.4. Emanuela V. Volpi1 et al. Journal of Cell Science 113, 1565-1576 . 2000.
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Chromosome spatial organization
Internal vs.
peripherial Relative
positions
Translocations
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Internal vs. peripheral
Change the position of genes during differentiation
Changes in transcriptional activity and gene density
Fig.2 Masahiko Kuroda et al. Journal of Cell Science. 117, 5897-5903, 2004.
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Relative position
Fig. 3. Tom Misteli. Cell. 128, 787–800, 2007
Functional consequences of Global chromatin organization
Separate chromosomes into physical proximity
sharing transcription sites.
Separate chromosomes into physical interaction corregulating gene loci.
Trans-regulation.
Relative position important determinant of function
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Translocations
Tissue-specific proximity of chromosomes correlates with tissue-specific translocation frequency
Fig. 3. Tom Misteli. Cell. 128, 787–800, 2007Fig.1. Luis A Parada et al. Genome Biology, Vo. 5, 7, R44. 2004
Tissue specific chromosomes organization
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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.
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Bibliography1. Alejandro Rodriguez et al. The links between chromatin spatial organization and biological
function. Biochemical Society Transactions . Vo. 41, p. 6, 2013.2. 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.
3. Lars Guelen et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. Vo. 453. 2008.
4. Luis A Parada et al. Tissue-specific spatial organization of genomes. Genome Biology, Vo. 5, 7, R44. 2004.
5. Masahiko Kuroda et al. Alteration of chromosome positioning during adipocyte differentiation. Journal of Cell Science. 117, 5897-5903, 2004.
6. 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.
7. T. Cremer and C. Cremer. Chromosome territories nuclear architecture and gene regulation in mammalian cells. Nature reviews . Vo. 2. 2001.
8. Tom Misteli. Beyond the Sequence: Cellular Organization of Genome Function. Cell. 128, 787–800, 2007.