Epigenetics: Chromatin fibre structure

Author: N. Gilbert
Submitted: Saturday 2nd of October 2010 07:50:46 AM
Submitted by: egf
Educational levels: expert, qc3

Abstract

In mammalian cells DNA is packaged with histone proteins to form chromatin – a macromolecular assembly. Most nuclear processes including DNA transcription, replication and repair occur in this chromatin environment and are influenced by the packaging of the chromatin fibre. We have a good knowledge of the fundamental building blocks of chromatin, the nucleosomes, but we know little about higher-levels of chromatin organisation. Nucleosomes are comprised of eight positively charged histone proteins that can be modified by a number of marks including acetylation, methylation and phosphorylation. Phosphorylation is important for facilitating the packaging of chromatin into higher order structures whilst the other marks can be thought of as molecular flags for marking the transcription status of different parts of the genome. In chromatin nucleosomes are regularly positioned along the DNA and this facilitates regular folding of the higher order chromatin fibre. However, if the positioning of nucleosomes is irregular then the higher order chromatin fibre will be more disorganised. Recently we have used high resolution nucleosome mapping to show that nucleosomes preferentially bind to GC rich DNA sequences. Therefore the underlying DNA can influence the organisation of the higher order chromatin fibre. Interestingly there is a high GC-content around promoters suggesting that the DNA sequence has evolved to tightly bind nucleosomes in specific positions near transcription start sites. We have now used an approach to investigate the higher order chromatin structure of genes. We have shown that genes have a clear chromatin disruption near their promoter and we think this facilitates recruitment of regulatory factors required for transcriptional activation. The magnitude of the promoter disruption increases during transcription consistent with the chromatin being remodelled and the chromatin in the body of the gene is also slightly disorganised consistent with the transcribing polymerase disrupting nucleosome positions. When a gene is being transcribed it becomes marked by certain histone modifications. These molecular “flags” can then promote the recruitment of other transcription factors or act as molecular docking sites for recruiting factors that might help to organise genes. One of these proteins, HP1 (heterochromatin protein 1) has a RNA binding domain and this might in turn recruit structural RNAs for stabilising the conformation of the chromatin fibre. Barski,A., Cuddapah,S., Cui,K., Roh,T.Y., Schones,D.E., Wang,Z., Wei,G., Chepelev,I., and Zhao,K. (2007). High-resolution profiling of histone methylations in the human genome. Cell. 129, 823-837. Boyle,A.P., Davis,S., Shulha,H.P., Meltzer,P., Margulies,E.H., Weng,Z., Furey,T.S., and Crawford,G.E. (2008). High-resolution mapping and characterization of open chromatin across the genome. Cell. 132, 311-322. Gilbert,N., Boyle,S., Fiegler,H., Woodfine,K., Carter,N.P., and Bickmore,W.A. (2004). Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers. Cell 118, 555-566. Gilbert,N. and Ramsahoye,B. (2005). The relationship between chromatin structure and transcriptional activity in mammalian genomes. Brief. Funct. Genomic. Proteomic. 4, 129-142. Gilbert,N., Gilchrist,S., and Bickmore,W.A. (2005). Chromatin organization in the mammalian nucleus. Int. Rev. Cytol. 242:283-336., 283-336. Gilbert,N. and Bickmore,W.A. (2006). The relationship between higher-order chromatin structure and transcription. Biochem. Soc. Symp. 59-66. Heintzman,N.D., Hon,G.C., Hawkins,R.D., Kheradpour,P., Stark,A., Harp,L.F., Ye,Z., Lee,L.K., Stuart,R.K., Ching,C.W., Ching,K.A., ntosiewicz-Bourget,J.E., Liu,H., Zhang,X., Green,R.D., Lobanenkov,V.V., Stewart,R., Thomson,J.A., Crawford,G.E., Kellis,M., and Ren,B. (2009). Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature. 459, 108-112. Schones,D.E., Cui,K., Cuddapah,S., Roh,T.Y., Barski,A., Wang,Z., Wei,G., and Zhao,K. (2008). Dynamic regulation of nucleosome positioning in the human genome. Cell. 132, 887-898. Sumner,A.T. (2003). Chromosomes : Organization and Function. Blackwell Scientific). Van Holde,K.E. (1988). Chromatin. (New York: Springer Verlag). Wolffe,A.P. (1998). Chromatin structure and function. (London: Academic Press). Zhao,X.D., Han,X., Chew,J.L., Liu,J., Chiu,K.P., Choo,A., Orlov,Y.L., Sung,W.K., Shahab,A., Kuznetsov,V.A., Bourque,G., Oh,S., Ruan,Y., Ng,H.H., and Wei,C.L. (2007). Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell. 1, 286-298.

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Citation

N. Gilbert. Epigenetics: Chromatin fibre structure. EUROGENE portal. October 2010. online: http://eurogene.open.ac.uk/content/epigenetics-chromatin-fibre-structure

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