Efficiency of Xist-mediated silencing on autosomes is linked to chromosomal domain organisation

Tang, Y. Amy; Huntley, Derek; Montana, Giovanni; Cerase, Andrea; Nesterova, Tatyana B.; Brockdorff, Neil

doi:10.1186/1756-8935-3-10

Cited by 58 publications

(68 citation statements)

References 39 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Functional Domains In Xist Rnasupporting

confidence: 82%

Chromosome silencing mechanisms in X-chromosome inactivation: unknown unknowns

Brockdorff

2011

Development

Self Cite

View full text Add to dashboard Cite

SummaryFifty years ago, Mary Lyon hypothesised that one of the two X chromosomes in female mammalian cells is inactivated at random during early embryogenesis and that the inactive X is then stably maintained through all subsequent cell divisions. Although Lyon's hypothesis is now widely regarded as fact, we should not forget that her conceptual leap met with considerable resistance from the scientific establishment at the time -a common response to new ideas. Taking this point as a theme, I discuss our current understanding of the molecular mechanism of chromosome silencing in X-chromosome inactivation and focus on topics where new findings are challenging the prevailing view.Key words: Chromatin, Epigenetics, X inactivation, Xist, X chromosome Introduction X-chromosome inactivation (XCI) is the process that has evolved in mammals to equalise the dosage of X-linked genes in XX females relative to XY males. Cells of early XX mammalian embryos silence a single X chromosome. Once established, chromosome silencing is stable and heritable through subsequent cell divisions, representing a classical example of epigenetic regulation.Mary Lyon proposed her XCI hypothesis 50 years ago (Lyon, 1961). Her idea raised two major questions: how do cells of the early embryo appropriately regulate XCI such that only one of the two X chromosomes in female cells is selected; and what is the mechanism for the stable and heritable silencing of genes along the entire chromosome? With the discovery in 1991 of X inactive specific transcript (Xist), the master regulator of XCI (Brown et al., 1991), these questions translate broadly into: what mechanisms underlie the developmental regulation of Xist expression; and how does Xist RNA coating trigger chromosome-wide silencing?This year has seen a number of reviews of the field published to celebrate the fiftieth anniversary of Mary Lyon's landmark discovery (Morey and Avner, 2011;Pontier and Gribnau, 2011;Wutz, 2011). In trying to conjure up something original to say, I found myself reflecting on the now infamous quote from the US politician Donald Rumsfeld regarding 'known knowns', 'known unknowns' and 'unknown unknowns'. Although often ridiculed, Rumsfeld's quote in fact makes some sense and one could certainly apply it to scientific research. In this case, the definition of known knowns and known unknowns is fairly self explanatory: questions for which we are certain of the answer and questions that we know represent gaps in our knowledge, respectively. The definition of unknown unknowns is less obvious, but we can generalise two categories: things that we have never conceived of; and things we think we know but are in fact incorrect and are therefore in reality unknown. The latter can be especially difficult to uncover because of the belief that we already know the answer, which deters serious examination of the alternatives. There are, however, tell-tale signs that can help -small clues, an accumulation of nagging inconsistencies. The natural tendency is to try to rationalise these ob...

show abstract

Section: Functional Domains In Xist Rnasupporting

confidence: 82%

Chromosome silencing mechanisms in X-chromosome inactivation: unknown unknowns

Brockdorff

2011

Development

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previous analyses have shown that relatively few autosomal, as compared with X-linked, genes are silenced in X/autosome translocations (White et al, 1998;Sharp et al, 2002); preliminary analysis from the Brown laboratory suggests that this might correlate with higher concentrations of LINE-1 elements near genes that are subject to inactivation. The implication of LINEs in XCI efficiency is consistent with another hypothesis proposed by Mary Lyon -that LINEs might represent way stations for XCI (Lyon, 1998) -which was recently supported by studies in mouse ES cells (Chow et al, 2010;Tang et al, 2010). The LINE-enrichment of the X chromosome in humans and mice (Boyle et al, 1990;Bailey et al, 2000) (but not marsupials, see below) supports the idea that such elements might indeed have been selectively retained in the course of evolution to facilitate XCI, at least in eutherians.…”

Section: Chromosome-wide Silencing and Escapesupporting

confidence: 85%

“…By contrast, the mechanism of binding and propagation of Xist RNA along the Xi remains poorly understood, although recent insights implicate Yin Yang 1 (YY1) as a possible candidate protein for bridging Xist RNA to its own locus (Jeon and Lee, 2011). The roles of nuclear scaffold proteins and of the local chromatin environment also appear crucial (Chow et al, 2010;Hasegawa et al, 2010;Tang et al, 2010). However, many unanswered questions still remain.…”

mentioning

confidence: 99%

Fifty years of X-inactivation research

Gendrel

Heard

2011

Development

View full text Add to dashboard Cite

The third X-inactivation meeting 'Fifty years of X-inactivation research', which celebrated the fiftieth anniversary of Mary Lyon's formulation of the X-inactivation hypothesis, was an EMBO workshop held in Oxford, UK, in July 2011. This conference brought together the usual suspects from the field, as well as younger researchers, to discuss recent advances in Xinactivation research. Here, we review the results presented at the meeting and highlight some of the exciting progress that has been made. We also discuss the future challenges for the field, which aim to further our understanding of the developmental regulation of X inactivation, the randomness (or skewing) of X inactivation, and the diverse strategies used by mammalian species to mediate X inactivation.

show abstract

“…This required a system in which Xist RNA expression could be induced synchronously and in a high proportion of cells. We therefore made use of a previously characterized mouse ES cell line, 3E, that carries a doxycycline-inducible Xist transgene integrated on chromosome 17 (30) (Fig. 1A).…”

Section: Prc2 Is Recruited To Chromosome 17 Gene-rich Domains In Respmentioning

confidence: 99%

Spatial separation of Xist RNA and polycomb proteins revealed by superresolution microscopy

Cerase

Smeets

Tang

et al. 2014

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

Self Cite

100

View full text Add to dashboard Cite

In female mammals, one of the two X chromosomes is transcriptionally silenced to equalize X-linked gene dosage relative to XY males, a process termed X chromosome inactivation. Mechanistically, this is thought to occur via directed recruitment of chromatin modifying factors by the master regulator, X-inactive specific transcript (Xist) RNA, which localizes in cis along the entire length of the chromosome. A well-studied example is the recruitment of polycomb repressive complex 2 (PRC2), for which there is evidence of a direct interaction involving the PRC2 proteins Enhancer of zeste 2 (Ezh2) and Supressor of zeste 12 (Suz12) and the A-repeat region located at the 5′ end of Xist RNA. In this study, we have analyzed Xist-mediated recruitment of PRC2 using two approaches, microarraybased epigenomic mapping and superresolution 3D structured illumination microscopy. Making use of an ES cell line carrying an inducible Xist transgene located on mouse chromosome 17, we show that 24 h after synchronous induction of Xist expression, acquired PRC2 binding sites map predominantly to generich regions, notably within gene bodies. Paradoxically, these new sites of PRC2 deposition do not correlate with Xist-mediated gene silencing. The 3D structured illumination microscopy was performed to assess the relative localization of PRC2 proteins and Xist RNA. Unexpectedly, we observed significant spatial separation and absence of colocalization both in the inducible Xist transgene ES cell line and in normal XX somatic cells. Our observations argue against direct interaction between Xist RNA and PRC2 proteins and, as such, prompt a reappraisal of the mechanism for PRC2 recruitment in X chromosome inactivation.

show abstract

Efficiency of Xist-mediated silencing on autosomes is linked to chromosomal domain organisation

Cited by 58 publications

References 39 publications

Chromosome silencing mechanisms in X-chromosome inactivation: unknown unknowns

Chromosome silencing mechanisms in X-chromosome inactivation: unknown unknowns

Fifty years of X-inactivation research

Spatial separation of Xist RNA and polycomb proteins revealed by superresolution microscopy

Contact Info

Product

Resources

About