Tissue-specific and allele-specific replication timing control in the imprinted human Prader-Willi syndrome region.

Gunaratne, Preethi H.; Nakao, Mitsuyoshi; Ledbetter, D H; Sutcliffe, James S.; Chinault, A. Craig

doi:10.1101/gad.9.7.808

Cited by 73 publications

(55 citation statements)

References 38 publications

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“…A variety of investigations have confirmed the association between the replication timing of a locus and its transcriptional activity (23)(24)(25). Expressed loci have been found to replicate early in S phase, whereas nonexpressing loci replicate late in S phase.…”

Section: Discussionmentioning

confidence: 94%

Epigenetic abnormalities associated with a chromosome 18(q21-q22) inversion and a Gilles de la Tourette syndrome phenotype

State

Greally²,

Cuker

et al. 2003

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

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Gilles de la Tourette syndrome (GTS) is a potentially debilitating neuropsychiatric disorder defined by the presence of both vocal and motor tics. Despite evidence that this and a related phenotypic spectrum, including chronic tics (CT) and Obsessive Compulsive Disorder (OCD), are genetically mediated, no gene involved in disease etiology has been identified. Chromosomal abnormalities have long been proposed to play a causative role in isolated cases of GTS spectrum phenomena, but confirmation of this hypothesis has yet to be forthcoming. We describe an i(18q21.1-q22.2) inversion in a patient with CT and OCD. We have fine mapped the telomeric aspect of the rearrangement to within 1 Mb of a previously reported 18q22 breakpoint that cosegregated in a family with GTS and related phenotypes. A comprehensive characterization of this genomic interval led to the identification of two transcripts, neither of which was found to be structurally disrupted. Analysis of the epigenetic characteristics of the region demonstrated a significant increase in replication asynchrony in the patient compared to controls, with the inverted chromosome showing delayed replication timing across at least a 500-kb interval. These findings are consistent with long-range functional dysregulation of one or more genes in the region. Our data support a link between chromosomal aberrations and epigenetic mechanisms in GTS and suggest that the study of the functional consequences of balanced chromosomal rearrangements is warranted in patients with phenotypes of interest, irrespective of the findings regarding structurally disrupted transcripts.

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Section: Discussionmentioning

confidence: 94%

Epigenetic abnormalities associated with a chromosome 18(q21-q22) inversion and a Gilles de la Tourette syndrome phenotype

State

Greally²,

Cuker

et al. 2003

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

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“…Using this method it was clearly shown that a pair of alleles which are known to be expressed concomitantly replicate synchronously, [10][11][12][13] whilst alleles subjected to some mechanism leading to alelle-specific expression, such as imprinting, 11,[14][15][16] X chromosome inactivation, 12 or some other allelic inactivation, 13,17 replicate asynchronously.…”

Section: Introductionmentioning

confidence: 99%

Asynchronous replication of allelic loci in Down syndrome

et al. 1998

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We have used FISH to determine the level of sychronisation in replication timing of four pairs of alleles, unrelated to chromosome 21 (p53, HER2, RB1, and c-myc), in foetal (amniotic fluid) cell samples of Down syndrome and in normal foetuses. All samples derived from the Down syndrome subjects showed large temporal differences in replication timing, in contrast to the high level of synchrony shown in all samples of normal individuals. Thus, as judged by four independent loci which are not associated with chromosome 21, the additional chromosome in the Down syndrome genome induces changes in the replication pattern of an allelic pair: from a synchronous pattern characteristic to concomitantly expressed alleles to an unsychronised one shown by alleles displaying an allele-specific mode of expression.

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“…The leading candidate is DNA methylation that is established in different patterns in the male and female germ lines and is maintained throughout embryogenesis to regulate the imprinted state. There are other epigenetic differences between the parental alleles of imprinted genes, including differential sensitivity of chromatin to nuclease digestion, asynchronous replication, and differential frequencies of meiotic recombination (5,13,18,24,25,39), but these are thought to be the consequences of the primary epigenetic mark, not the causes.…”

mentioning

confidence: 99%

Multiple Mechanisms Regulate Imprinting of the Mouse Distal Chromosome 7 Gene Cluster

Caspary

Cleary

Baker

et al. 1998

Molecular and Cellular Biology

223

166

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Genomic imprinting is an epigenetic process that results in the preferential silencing of one of the two parental copies of a gene. Although the precise mechanisms by which genomic imprinting occurs are unknown, the tendency of imprinted genes to exist in chromosomal clusters suggests long-range regulation through shared regulatory elements. We characterize a 800-kb region on the distal end of mouse chromosome 7 that contains a cluster of four maternally expressed genes, H19, Mash2, Kvlqt1, and p57 Kip2 , as well as two paternally expressed genes, Igf2 and Ins2, and assess the expression and imprinting of Mash2, Kvlqt1, and p57Kip2 during development in embryonic and extraembryonic tissues. Unlike Igf2 and Ins2, which depend on H19 for their imprinting, Mash2, p57 Kip2, and Kvlqt1 are unaffected by a deletion of the H19 gene region, suggesting that these more telomeric genes are not regulated by the mechanism that controls H19, Igf2, and Ins2. Mutations in human p57Kip2 have been implicated in Beckwith-Wiedemann syndrome, a disease that has also been associated with loss of imprinting of IGF2. We find, however, that a deletion of the gene has no effect on imprinting within the cluster. Surprisingly, the three maternally expressed genes are regulated very differently by DNA methylation; p57Kip2 is activated, Kvlqt1 is silenced, and Mash2 is unaffected in mice lacking DNA methyltransferase. We conclude that H19 is not a global regulator of imprinting on distal chromosome 7 and that the telomeric genes are imprinted by a separate mechanism(s).

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Tissue-specific and allele-specific replication timing control in the imprinted human Prader-Willi syndrome region.

Cited by 73 publications

References 38 publications

Epigenetic abnormalities associated with a chromosome 18(q21-q22) inversion and a Gilles de la Tourette syndrome phenotype

Epigenetic abnormalities associated with a chromosome 18(q21-q22) inversion and a Gilles de la Tourette syndrome phenotype

Asynchronous replication of allelic loci in Down syndrome

Multiple Mechanisms Regulate Imprinting of the Mouse Distal Chromosome 7 Gene Cluster

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