Human autoimmune sera recognize a conserved 26 kD protein associated with mammalian heterochromatin that is homologous to heterochromatin protein 1 ofDrosophila

Nicol, Linda; Jeppesen, Peter

doi:10.1007/bf01553325

Cited by 56 publications

(42 citation statements)

References 35 publications

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“…Understanding of heterochromatin has recently been improved by the isolation of some of its constituent proteins (7,11,23,32). It is possible that MeCP2 represents part of a complex of proteins involved in the formation and maintenance of heterochromatin in mouse cells, particularly in differentiated cell types.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Specifies Chromosomal Localization of MeCP2

Nan

Täte

et al. 1996

Molecular and Cellular Biology

307

229

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MeCP2 is a chromosomal protein that is concentrated in the centromeric heterochromatin of mouse cells. In vitro, the protein binds preferentially to DNA containing a single symmetrically methylated CpG. To find out whether the heterochromatic localization of MeCP2 depended on DNA methylation, we transiently expressed MeCP2-LacZ fusion proteins in cultured cells. Intact protein was targeted to heterochromatin in wild-type cells but was inefficiently localized in mutant cells with low levels of genomic DNA methylation. Deletions within MeCP2 showed that localization to heterochromatin required the 85-amino-acid methyl-CpG binding domain but not the remainder of the protein. Thus MeCP2 is a methyl-CpG-binding protein in vivo and is likely to be a major mediator of downstream consequences of DNA methylation.Widespread methylation of genomic DNA is a characteristic of the vertebrates. The target of methylation is the dinucleotide CpG, which acquires a methyl group at the 5 position on the cytosine ring. Functions of methylation have long been the subject of experiment and speculation, but recent experiments provide evidence for an essential role in development. Li et al. (16) disrupted the gene that encodes the DNA methyltransferase (MTase) enzyme in mice and found that homozygous mutant embryos had greatly reduced levels of methylation, were developmentally retarded, and died at midgestation. Undifferentiated embryonic stem (ES) cells, on the other hand, behaved normally in culture, despite very low levels of methylation, indicating that methylation may be less important at this totipotent stage. Why methylation is essential for development is not yet completely clear. One possibility is that methylation-mediated repression of genes is somehow built into the developmental program (discussed in reference 1).To understand the biology of DNA methylation, it is necessary to identify all components of the system. Several proteins that bind specifically to methylated DNA are known (reviewed in reference 31). Two of these, MeCP1 and MeCP2, bind to symmetrical methyl-CpG pairs in any sequence context and may therefore be of general significance (14,17,18). Studies of MeCP1 have implicated it in methylation-mediated gene inactivation (2, 3). The second protein, MeCP2, consists of a single chain of 492 amino acids in the rat, including an 85-amino-acid domain near the N terminus that encodes all of the specificity required for binding to methylated DNA (22). The mouse protein (484 amino acids) is very similar to its rat homolog, showing an overall identity of 95% at the amino acid level and absolute conservation of the methylated DNA binding domain (29). This methyl-CpG binding domain (MBD) can bind as a monomer to a single symmetrically methylated CpG pair. Immunofluorescence analysis of mouse chromosomes shows that MeCP2 is preferentially localized in pericentromeric heterochromatin (14), which is also the region of highest 5-methylcytosine concentration (19). The predominant DNA sequence in mouse heterochromatin is the m...

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Section: Discussionmentioning

confidence: 99%

DNA Methylation Specifies Chromosomal Localization of MeCP2

Nan

Täte

et al. 1996

Molecular and Cellular Biology

307

229

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“…Therefore these antigens were classified as non-centromeric. Recently, it has been shown that affinity-purified autoantibodies from blotted 25-kD protein are concentrated in pericentromeric heterochromatin by in situ immunolabelling [21]. Anti-23-kD protein (p23) and -25-kD protein (p25) antibodies have cross-reactivity [20].…”

Section: Introductionmentioning

confidence: 99%

Clinical features of anti-chromo antibodies associated with anti-centromere antibodies

Iwai

Muro

Sugimoto

et al. 1996

Clinical and Experimental Immunology

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SUMMARYAnti-chromo antibodies (AChA) are autoantibodies accompanying anti-centromere antibodies (ACA). We determined the frequency and clinical significance of AChA in autoimmune rheumatic diseases. Serum samples from 252 patients with rheumatic diseases were examined by immunoblotting with HeLa nuclear extract and with recombinant N-terminus of 25-kD chromo protein (p25). AChA were detected in 28 (36%) of 77 sera with ACA. AChA were found only in ACA-positive sera. Twenty-two (79%) of 28 recognized a recombinant N-terminal portion of p25, including the chromo domain which is conserved among species. AChA were related to leucopenia, thrombocytopenia, elevated erythrocyte sedimentation rate, and existence of Sjögren's syndrome (SS). In ACA-positive patients, AChA might be a serologic indicator of systemic sclerosis (SSc), having features of systemic lupus erythematosus and/or SS or diseases other than SSc.

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“…Mutant forms of Drosophila HP1 act as suppressors of variegating genes, whereas overexpression results in enhanced repression (Eissenberg et al 1992}. Several chromodomain proteins have been found associated with centromeric heterochromatin Saunders et al 1993;Nicol and Jeppesen 1994;Wreggett et al 1994). Similarly, Polycomb is required to maintain repression of homeotic genes during development (Paro 1993}.…”

mentioning

confidence: 99%

Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation.

Allshire¹,

Nimmo²,

Ekwall³

et al. 1995

Genes Dev.

436

393

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The ura4 + gene displays phenotypes consistent with variegated expression when inserted at 11 sites throughout fission yeast centromere 1. An abrupt transition occurs between the zone of centromeric repression and two adjacent expressed sites. Mutations in six genes alleviate repression of the silent-mating type loci and of ura4 + expressed from a site adjacent to the silent locus, mat3-M. Defects at all six loci affect repression of the ara4 + gene adjacent to telomeres and at the three centromeric sites tested. The clr4-$5 and rikl-304 mutations cause the most dramatic derepression at two out of three sites within cenl. All six mutations had only slight or intermediate effects on a third site in the center of cenl or on telomeric repression. Strains with lesions at the clr4, rikl, and swi6 loci have highly elevated rates of chromosome loss. We propose that the products of these genes are integral in the assembly of a heterochromatin-like structure, with distinct domains, enclosing the entire centromeric region that reduces or excludes access to transcription factors. The formation of this heterochromatic structure may be an absolute requirement for the formation of a fully functional centromere.[Key Words: S. pombe; PEV; heterochromatin; telomere; mating type] Received October 7, 1994; revised version accepted December 13, 1994.The centromeres of the fission yeast Schizosaccharomyces pombe are complex structures composed of large repetitive arrays symmetrically arranged around a nonrepetitive central domain (Hahnenberger et al. 1991;Murakami et al. 1991;Takahashi et al. 1992;Steiner et al. 1993; cenl is shown in Fig. 1A, below). Long arrays of tandem satellite repeats are frequently associated with the centromeres of many eukaryotes (Miklos and Cotsell 1990;Rattner 1991;Tyler-Smith and Willard 1993). These centromeric satellites are packaged into a highly compacted structure known as constitutive heterochromatin, but it is not known if this contributes to centromere function. It is likely that mammalian satellite repeats contribute to kinetochore formation, but alone, they may not be sufficient to form a functional centromere (Earnshaw et al. 1989;Haaf et al. 1992;Larin et al. 1994).Genes placed in the vicinity of centromeric heterochromatin in mouse cells can exhibit variable states of expression (Butner and Lo 1986). This phenomenon, termed position effect variegation (PEV), was first described in Drosophila, where it was found that genes placed adjacent to centromeric heterochromatin were unstably repressed (Eissenberg 1989;Henikoff 1990;Karpen 1994). In Drosophila, mouse, and human cells, some 1Corresponding author. studies indicate that heterochromatin is often associated with the nuclear periphery (Hochstrasser et al. 1986;Ferguson and Ward 1992;Vourc'h et al. 1993). It is possible that this and other associations serve to lock these regions of chromosomes in an inactive state (Karpen 1994}. In unicellular organisms, such as yeasts, there are chromosomal regions with features characteristic of heterochro...

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Human autoimmune sera recognize a conserved 26 kD protein associated with mammalian heterochromatin that is homologous to heterochromatin protein 1 ofDrosophila

Cited by 56 publications

References 35 publications

DNA Methylation Specifies Chromosomal Localization of MeCP2

DNA Methylation Specifies Chromosomal Localization of MeCP2

Clinical features of anti-chromo antibodies associated with anti-centromere antibodies

Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation.

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