Nuclear architecture - an epigenetic mechanism for the regulation of nuclear functions

Author: M. Cremer
Submitted: Sunday 5th of September 2010 09:13:21 AM
Submitted by: egf
Educational levels: expert, qc3

Abstract

Increasing attention has been paid in the last years to the functional relevance of 3D genome organisation in the nucleus as an epigenetic mechanism of gene regulation beyond regulatory sequences and local chromatin configuration. This concerns e.g. the positioning of genome loci with regard to a specific nuclear compartment, changes of higher order chromatin arrangement during (terminal) differentiation or the spatial repositioning of distinct gene loci in relation to their transcriptional activity. The human DNA sequence is organized in segments of low and high gene density, (some of them representing regions of ubiquitously increased gene expression, so called RIDGES), of different replication timing and DNA composition. Along metaphase chromosomes these segmental differences of chromatin features are reflected by characteristic chromosome specific banding patterns, such as G-dark (G) and G-light (R) bands, representing differences in DNA base composition, chromatin folding and compactness. In interphase nuclei of metazoa, chromosomes are organized as chromosome territories (CTs) with an irregular shape and variable density and the segmental organisation of metaphase chromosomes is transposed into a polar organisation: Interphase chromatin tends to be spatially arranged in a distinct radial pattern with the preferential localization of gene-dense and early replicating chromatin respectively in the nuclear interior and of gene-poor and later replicating chromatin at the nuclear envelope. Such patterns have been found evolutionary conserved over several hundred millions of years, illustrating that the radial arrangement of chromatin in the interphase nucleus represents a basic principle of nuclear architecture and pointing to a functional relevance in the context of epigenetic mechanisms of gene regulation. The functional meaning for the enrichment of gene dense chromatin in the nuclear interior and of gene poor chromatin at the nuclear envelope and the mechanisms, that initiate and maintain such a polarized organization are, however, not yet disclosed. The spatial proximity of genes in the nuclear interior may facilitate their temporal transcriptional coordination irrespective of their location on different chromosomes and may help to establish a chromatin topography, which optimally suits the structural requirements for transcription, mediated by interactions between chromatin and protein complexes. For highly transcribed genes activation or silencing has been associated with repositioning of the locus relative to nuclear compartments and other genomic loci. In this context the observation of global reorganization of the genome in early (bovine) embryos in correlation to transcriptional activation is also of interest. That an enrichment of genes in the nuclear interior (and concomitant transcriptional activity) is not mandatory, however, was recently shown by the unexpected observation of an “inverted” pattern of higher order chromatin arrangements in rod cell nuclei of adult animals of different nocturnal species (such as mouse and cat). While rod cell nuclei in the retina of newborns still display the “conventional” nuclear architecture, a remodeling into an “inverted” pattern takes place during the postmitotic, terminal differentiation. In these cells chromatin poised for transcription, as well as highly transcribed genes are located in the nuclear periphery and gene-poor chromatin (heterochromatin) at the nuclear center. In contrast, rod cell nuclei of diurnal species maintain the “conventional” pattern described above. This unique organization suggests a functional significance of cell type specific differences of the nuclear architecture in the retina of mammals based on physical properties of chromatin, which was confirmed by computer simulations: An “inverted” chromatin arrangement is less diffractive to light and therefore provides an advantage for nocturnal animals. Finally the controverse discussion about the existence of an interchromatin / perichromatin compartment as specific functional compartments for replication, transcription and RNA processing will be addressed. Ths topic concerns basic structural organization of chromatin arrangement in the nucleus References: Cremer T, Cremer M, Dietzel S, Müller S, Solovei I Fakan S (2006) Chromosome territories – a functional nuclear landscape. Current Opinion in Cell Biology 18: 307-316 Misteli T, Dernburg AF (2007) Beyond the sequence: cellular organization of genome function. Cell 128: 787-800 Küpper K, Kölbl A, Biener D, Dittrich S, v. Hase J, Thormeyer T, Fiegler H, Carter N, Speicher MR, Cremer T, Cremer M (2007) Radial chromatin positioning is shaped by local gene density not by gene expression. Chromosoma 116: 285-306 Lanctôt C, Cheutin T, Cremer M, Cavalli G, Cremer T (2007) Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions (2007). Nature Rev Genet 8: 105-115 Fraser, P, Bickmore W (2007) Nuclear organization of the genome and the potential for gene regulation. Nature 447: 413-417 Solovei, I, Kreysing M, Lanctot C, Koesem S, Peichl L, Cremer T, Guck J, Joffe B. (2009) Nuclear Architecture of Rod Photoreceptor Cells Adapts to Vision in Mammalian Evolution. Cell 137: 356-368 Koehler D, Zakhartchenko V, Froenicke L, Stone G, Stanyon R, Wolf E, Cremer T, Brero A (2009). Changes of higher order chromatin arrangements during major genome activation in bovine preimplantation embryos. Exp. Cell Res. 315: 2053-63

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M. Cremer. Nuclear architecture - an epigenetic mechanism for the regulation of nuclear functions. EUROGENE portal. September 2010. online: http://eurogene.open.ac.uk/content/nuclear-architecture-epigenetic-mechanism-regulation-nuclear-functions

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