Attenuated spread of X-inactivation in an X;autosome translocation

Abstract

X inactivation in female mammals involves transcriptional silencing of an entire chromosome in response to a cis-acting noncoding RNA, the X inactive-specific transcript (Xist). Xist can also inactivate autosomal sequences, for example, in X;autosome translocations; but here, silencing appears to be relatively inefficient. This variation has been attributed to either attenuated spreading of Xist RNA at the onset of X inactivation or inefficient maintenance of autosomal silencing. Evidence to date has favored the latter. Here, we demonstrate attenuated spreading of Xist RNA at the onset of X inactivation in the T(X;4)37H X;autosome translocation. Our findings provide direct evidence that underlying chromosome͞chro-matin features can disrupt spreading of the primary inactivating signal.line-1 ͉ Xist X inactivation is the dosage compensation mechanism in female mammals. In early embryogenesis both X chromosomes are active. Transcriptional silencing of a single X chromosome then proceeds, coincident with the onset of cellular differentiation. Normally X inactivation occurs randomly, there being an equal probability that either the maternally or paternally derived X chromosome will be inactivated in a given cell. The inactive state is stable and is maintained through subsequent cell divisions (reviewed in ref. 1).X inactivation is regulated by a single cis-acting master control locus, the X inactivation center (Xic). The Xic transcribes a noncoding RNA, the X inactive-specific transcript (Xist), which associates along the length of the chromosome from which it is transcribed (2-7). Spreading of Xist RNA leads to conversion of the chromosome to a silent heterochromatic configuration. This X inactivation involves multiple epigenetic changes, including covalent modification of core histone tails, incorporation of variant histones, and DNA methylation (reviewed in ref. 8).It is important to understand how Xist RNA propagates or spreads from the Xic along the entire length of the X chromosome. Classical genetic analysis of X;autosome (X;A) translocations has demonstrated that autosomal loci linked in cis to the Xic are inactivated less efficiently than normal X-linked genes (9, 10). It has been suggested that this variation is due to either attenuated spreading of silencing at the onset of X inactivation in early development or failure to efficiently maintain autosomal silencing through ontogeny, referred to as ''spread and retreat.'' These two models are not mutually exclusive, but evidence to date favors spread and retreat. Specifically, studies using Cattanachs' translocation, Is(X;7)1ct, an insertion of a region of chromosome 7 into the X chromosome, demonstrated initial spread and subsequent retreat of silencing at the albino (c) locus present within the insertion (10). Additionally, studies using Xist transgenes located in autosomes have reported efficient spread of Xist RNA (11, 12), which does not support the argument for the ''attenuated spread'' model. Set against this background, indirect cytogenetic analysis o...

Chromosome silencing mechanisms in X-chromosome inactivation: unknown unknowns

“…3B). This view would be consistent with accumulating evidence that proteins that modulate higher order chromosomal organisation, such as Satb1, Smchd1 and hnRNPU (Agrelo et al, 2009;Blewitt et al, 2008;Hasegawa et al, 2010), and/or the chromosomal distribution of LINE-1 elements (Chow et al, 2010;Popova et al, 2006;Tang et al, 2010), play a key role in Xist RNA propagation and/or chromosome silencing. It will be interesting to extend the analysis of inducible Xist transgenes, both WT and mutant, applying RNA-seq of nuclear RNA to quantify allelic expression using SNPs in interspecific hybrid cell lines.…”

Cellular and molecular effects of nonreciprocal chromosome translocations in Saccharomyces cerevisiae

“…These conclusions are corroborated by results from mammalian cell cultures, in which the effects of translocation are observed well after its occurrence. For instance, an X chromosome-autosome translocation led to spreading of the X chromosomal gene silencing effect on autosomal genes (25). Moreover, in some Burkitt's lymphoma patients, c-Myc expression was activated by juxtaposition to the Ig heavy-chain gene HS3 enhancer, which actually had increased histone-3 and histone-4 acetylation on P1 c-Myc promoter via the recruitment of the CBP histone acetylase (26).…”

Two Classes of Dosage Compensation Complex Binding Elements along Caenorhabditis elegans X Chromosomes

“…When a portion of the X not containing the XIC/Xic region is translocated to an autosome, this chromosomal region will not be bound by Xist and will not be subjected to dosage compensation. However, when the X-inactivation center is moved adjacent to autosomal sequences (either on X-autosomal translocations, or Xic transgenes inserted on autosomes), variable and incomplete spreading into the autosomal region has been observed (8,20,30,32,33,35). These types of observations led to the "way station" hypothesis, originally proposed by Gartler and Riggs (12).…”