[雙語翻譯]醫(yī)學(xué)外文翻譯---自身免疫表觀遺傳學(xué)（英文）

1、The epigenetics of autoimmunityFrancesca Meda1,2, Marco Folci1, Andrea Baccarelli3, and Carlo Selmi1,21 Department of Medicine and Hepatobiliary Immunopathology Unit, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Ita

2、ly2 Department of Translational Medicine, University of Milan, Rozzano, Milan, Italy3 Harvard School of Public Health, Exposure, Epidemiology Tel +39.02.8224.5129; Fax +39.02.8224.4590; carlo.selmi@unimi.it.NIH Public A

3、ccess Author Manuscript Cell Mol Immunol. Author manuscript; available in PMC 2011 May 13.Published in final edited form as: Cell Mol Immunol. 2011 May ; 8(3): 226–236. doi:10.1038/cmi.2010.78.NIH-PA Author Manuscript NI

4、H-PA Author Manuscript NIH-PA Author Manuscriptepigenetic changes known so far, and therefore their underlying processes will be discussed below in further details. Moreover, the newest field of microRNA will be briefly

5、illustrated as an additional gene regulatory mechanism.Histone modificationsAs mentioned before, histones are highly conserved proteins that reside within nuclei of eukaryotic cells. They can be classified into two main

6、groups: 1) core histones (H2A, H2B, H3, and H4) that are part of the nucleosome core, the basic unit of DNA packaging in eukaryotics, and 2) linker histones (H1, H5). Two of each of the core histones assemble to form an

7、octameric nucleosome core particle by wrapping about 147 base pairs of DNA around the protein spool in a 1.7 left-handed super-helical turn 9 (Figure 1), thus providing DNA condensation and organization in the nucleus, a

8、s well as modulating DNA accessibility to the transcription machinery. This latter process could be represented as a drawer that can be opened or closed following specific stimuli. In fact, each histone subtype can be mo

9、dified by different chemical modification at defined amino acids leading to transcription modulation and, therefore, cell cycle regulation, development, and differentiation.Each of the four core histones shares the same

10、folding structure known as histone fold domain (HFD), which consists of three α-helices (α1, α2, and α3) separated by two loops (L1 and L2) 10. The HFD fold together in antiparallel pairs (H3 with H4 and H2A with H2B) to

11、 constitute tetramers. The subsequent assembly of two tetramers forms the octameric core structure (H3/H4-H2A/H2B1) of the nucleosome 11. The N-terminal regions of histones protrude outside the nucleosome core and are pr

12、one to post-translational modifications, which are important in chromatin compaction and gene regulation. Histone post- translational modifications concur to determine the pattern defined as “histone code” and will be su

13、mmarized below. All these histone modifications are caused by specific enzymes which recognize histone tails and can work to add or remove functional groups which are in turn recognized by nuclear factors. Specific prote

14、ins have affinity for modified amino acid residues (for instance bromodomains bind acetylated lysines or chromodomains methylated lysines) and promote specific changes in chromatin determining respectively the activation

15、 or the silencing of gene transcription (Figure 2).Among histone modifications, acetylation or deacetylation are one of the most important gene expression regulatory mechanisms. These processes involve selected lysine re

16、sidues in the tails of nucleosomal histones and are induced by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes, respectively 12–15. HAT enzymes share the ability to promote gene expression by trans

17、ferring acetyl groups to lysine 16–18 while HDACs remove acetyl groups and generally associate with gene repression 19–21. A second mechanism involves histone methylation and its effects depend on the position of the mod

18、ified lysine residue within the histone tail and on the number of methyl groups added to such residues. As an example, the presence of three methyl groups on lysine 4 residue on histone H3 (Me- H3K4), has been associated

19、 with transcriptional activation whereas the triple methylation of residues 9 or 27 determines repression 3,22–26.As a third mechanism, arginine can also be methylated/demethylated by specific enzymes and play a critical

20、 role in the dynamic regulation of gene expression 27. Methylation of arginine residue 3 on histone H4 (H4R3) and arginine 17 on histone H3 (H3R17) have been shown to induce gene activation 23,28–30. Finally, ubiquitin i

21、s a 76 amino acid protein that is involved in specific protein labeling. Ubiquitinated proteins are committed to proteosomal degradation and ubiquitination thus controlling the stability and intracellular localization of

22、 numerous proteins. Ubiquitination ultimately influences the status of histones methylation orMeda et al. Page 3Cell Mol Immunol. Author manuscript; available in PMC 2011 May 13.NIH-PA Author Manuscript NIH-PA Author Man