A genome-derived (gaa.ttc)24 trinucleotide block binds nuclear protein(s) specifically and forms triple helices

Mäueler, Winfried; Kyas, Andreas; Keyl, Hans-Günther; Epplen, Jörg T.

doi:10.1016/s0378-1119(98)00266-2

Cited by 18 publications

(8 citation statements)

References 28 publications

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“…[AG] n has been strongly linked to chromatin regulation and is a polypurine/polypyrimidine motif (PP) capable of forming triplex DNA (Maueler et al 1998;Ohno et al 2002). Triplex DNA can link distant sequences and be either a positive or negative regulator of gene expression (Kohwi and Kohwi-Shigematsu 1991).…”

Section: Discussionmentioning

confidence: 99%

Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]_nin the X escape region

McNeil¹,

Smith²,

Hall³

et al. 2006

Genome Res.

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Most of the human genome encodes neither protein nor known functional RNA, yet available approaches to seek meaningful information in the "noncoding" sequence are limited. The unique biology of the X chromosome, one of which is silenced in mammalian females, can yield clues into sequence motifs involved in chromosome packaging and function. Although autosomal chromatin has some capacity for inactivation, evidence indicates that sequences enriched on the X chromosome render it fully competent for silencing, except in specific regions that escape inactivation. Here we have used a linguistic approach by analyzing the frequency and distribution of nine base-pair genomic "words" throughout the human genome. Results identify previously unknown sequence differences on the human X chromosome. Notably, the dinucleotide repeats [AT] n , [AC] n , and [AG] n are significantly enriched across the X chromosome compared with autosomes. Moreover, a striking enrichment (>10-fold) of [GATA] n is revealed throughout the 10-Mb segment at Xp22 that escapes inactivation, and is confirmed by fluorescence in situ hybridization. A similar enrichment is found in other eutherian genomes. Our findings clearly demonstrate sequence differences relevant to the novel biology and evolution of the X chromosome. Furthermore, they implicate simple sequence repeats, linked to gene regulation and unusual DNA structures, in the regulation and formation of facultative heterochromatin. Results suggest a new paradigm whereby a regional escape from X inactivation is due to the presence of elements that prevent heterochromatinization, rather than the lack of other elements that promote it.

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Section: Discussionmentioning

confidence: 99%

Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]_nin the X escape region

McNeil¹,

Smith²,

Hall³

et al. 2006

Genome Res.

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“…frataxin gene (11,27,28). In addition, while full expansions of the GAA tract inhibit transcription when evaluated in vitro (2,3,11), the question of whether heterozygous carriers of these GAA expansions show decreased expression of frataxin protein in vivo remains to be evaluated.…”

Section: A B Gaa Expansions and Insulin Resistancementioning

confidence: 99%

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

et al. 2000

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Friedreich's ataxia (FA) is an autosomal recessive disease that has been attributed to a GAA triplet repeat expansion in the first intron of the X25/frataxin gene. Impaired glucose tolerance is present in up to 39% of FA patients, and clinically apparent diabetes is seen in ~18% of the affected individuals. Subjects carrying the X25/frataxin GAA repeat in a heterozygous state do not develop FA and, therefore, represent an ideal model to study the underlying metabolic defects that contribute to the diabetes associated with this disorder. In the present study, we have compared 11 first-degree relatives of FA patients (i.e., parents or heterozygous siblings of FA patients) with matched normal control subjects to study the parameters of glucose metabolism. An oral glucose tolerance test revealed diabetes in one of the heterozygous subjects who was excluded from further analyses. Using an octreotide-based quantification of insulin sensitivity, 8 of the remaining 10 study subjects showed pronounced insulin resistance, reflecting a significant difference from the control group (P = 0.001). In conclusion, a heterozygous expansion of the X25/frataxin GAA repeat in healthy individuals is associated with insulin resistance and might be considered a genetic co-factor in the pathogenesis of mitochondrial subtypes of diabetes. Diabetes 49:1604-1607, 2000 F riedreich's ataxia (FA) is phenotypically characterized by progressive ataxia and other neurological alterations in association with hypertrophic cardiomyopathy. The vast majority of FA patients carry a homozygous expansion of an intronic GAA tract of the X25/frataxin gene (1) leading to interference with the transcription of the frataxin gene (2) and subsequently decreasing expression of the frataxin protein (3). Frataxin is expressed in a wide variety of tissues, exhibits mitchondrial localization, and appears to be essential for embryonic development (4) in mice. Frataxin is most abundant in tissues with high metabolic activity, including skeletal muscle and brown fat (5). The characterization of the yeast frataxin homolog suggests a central role in oxidative phosphorylation (6). Furthermore, frataxin was proposed to regulate mitochondrial iron content (7,8) and to decrease oxidative damage to the cell (9,10). Frataxin is a mitochondrial protein that is significantly reduced in FA patients because of decreased transcription subsequent to expanded intronic GAA repeats on both copies of the X25/frataxin gene. Heterozygous carriers for this expansion are phenotypically normal but presumably exhibit a decreased expression of frataxin (2,11). In the present study, these heterozygous individuals were evaluated for alterations in glucose metabolism, specifically incidence of diabetes and insulin resistance.First, first-degree relatives of FA patients were genotyped, as described in RESEARCH DESIGN AND METHODS, to assure the presence of GAA expansions, especially in siblings of the patients. Eleven subjects from 4 different unrelated families were analyzed (8 parents and 3 sibli...

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“…Frataxin is expressed in tissues with high metabolic activity, including brown fat, heart, liver, and certain neurons and neuroendocrine cells as found in the pancreas (9,11). In FA, expression of frataxin is severely reduced (12) because of inhibition of the transcriptional machinery by expansion of an intronic GAA repeat (8,(13)(14)(15)(16).…”

mentioning

confidence: 99%

Frataxin activates mitochondrial energy conversion and oxidative phosphorylation

Ristow

Pfister²,

Yee³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

211

162

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Friedreich's ataxia (FA) is an autosomal recessive disease caused by decreased expression of the mitochondrial protein frataxin. The biological function of frataxin is unclear. The homologue of frataxin in yeast, YFH1, is required for cellular respiration and was suggested to regulate mitochondrial iron homeostasis. Patients suffering from FA exhibit decreased ATP production in skeletal muscle. We now demonstrate that overexpression of frataxin in mammalian cells causes a Ca 2؉ -induced up-regulation of tricarboxylic acid cycle flux and respiration, which, in turn, leads to an increased mitochondrial membrane potential (⌬ m) and results in an elevated cellular ATP content. Thus, frataxin appears to be a key activator of mitochondrial energy conversion and oxidative phosphorylation.

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A genome-derived (gaa.ttc)24 trinucleotide block binds nuclear protein(s) specifically and forms triple helices

Cited by 18 publications

References 28 publications

Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]_nin the X escape region

Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]_nin the X escape region

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

Frataxin activates mitochondrial energy conversion and oxidative phosphorylation

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A genome-derived (gaa.ttc)24 trinucleotide block binds nuclear protein(s) specifically and forms triple helices

Cited by 18 publications

References 28 publications

Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]nin the X escape region

Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]nin the X escape region

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

Frataxin activates mitochondrial energy conversion and oxidative phosphorylation

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Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]_nin the X escape region

Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]_nin the X escape region