X Chromosomes Alternate between Two States prior to Random X-Inactivation

Mlynarczyk-Evans, Susanna; Royce-Tolland, Morgan; Alexander, Mary Kate; Andersen, Angela A.; Kalantry, Sundeep; Gribnau, Joost; Panning, Barbara

doi:10.1371/journal.pbio.0040159

Cited by 62 publications

(56 citation statements)

References 39 publications

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“…a differential cohesion of sister chromatids. In this regard, singletdoublet DNA FISH signals independent of asynchronous DNA replication, the so-called SIAR, have been described at the X chromosome center (Mlynarczyk-Evans et al, 2006). Again, this possibility is extremely unlikely because we failed to obtain any evidence for primary neurons arrested at the G2-M transition, as judged by the lack of duplicated centrosomes (not shown).…”

Section: Journal Of Cell Science 123 (1)mentioning

confidence: 83%

Long nuclear-retained non-coding RNAs and allele-specific higher-order chromatin organization at imprinted snoRNA gene arrays

Vitali

Royo

Marty

et al. 2010

Journal of Cell Science

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SummaryThe imprinted Snurf-Snrpn domain, also referred to as the Prader-Willi syndrome region, contains two ~100-200 kb arrays of repeated small nucleolar (sno)RNAs processed from introns of long, paternally expressed non-protein-coding RNAs whose biogenesis and functions are poorly understood. We provide evidence that C/D snoRNAs do not derive from a single transcript as previously envisaged, but rather from (at least) two independent transcription units. We show that spliced snoRNA host-gene transcripts accumulate near their transcription sites as structurally constrained RNA species that are prevented from diffusing, as well as multiple stable nucleoplasmic RNA foci dispersed in the entire nucleus but not in the nucleolus. Chromatin structure at these repeated arrays displays an outstanding parent-of-origin-specific higher-order organization: the transcriptionally active allele is revealed as extended DNA FISH signals whereas the genetically identical, silent allele is visualized as singlet DNA FISH signals. A similar allele-specific chromatin organization is documented for snoRNA gene arrays at the imprinted Dlk1-Dio3 domain. Our findings have repercussions for understanding the spatial organization of gene expression and the intra-nuclear fate of non-coding RNAs in the context of nuclear architecture.

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Section: Journal Of Cell Science 123 (1)mentioning

confidence: 83%

Long nuclear-retained non-coding RNAs and allele-specific higher-order chromatin organization at imprinted snoRNA gene arrays

Vitali

Royo

Marty

et al. 2010

Journal of Cell Science

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“…We first carried out this deletion in mouse F1 (Mus musculus 129 3 Mus castaneus) ES cells, allowing allele-specific deletion screening and gene expression analysis (Mlynarczyk-Evans et al 2006). We used two guide RNAs (gRNA 104 and gRNA 112 ) to generate the large deletion (Fig.…”

Section: The Scr Is Required For Sox2 Transcription In Es Cellsmentioning

confidence: 99%

“…Error bars represent standard deviation. some over the Cast X chromosome upon differentiation (Ogawa and Lee 2003;Mlynarczyk-Evans et al 2006).…”

Section: Srr1 Srr2 and Srr18 Are Not Required For Sox2 Transcriptiomentioning

confidence: 99%

A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential

et al. 2014

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The Sox2 transcription factor must be robustly transcribed in embryonic stem (ES) cells to maintain pluripotency. Two gene-proximal enhancers, Sox2 regulatory region 1 (SRR1) and SRR2, display activity in reporter assays, but deleting SRR1 has no effect on pluripotency. We identified and functionally validated the sequences required for Sox2 transcription based on a computational model that predicted transcriptional enhancer elements within 130 kb of Sox2. Our reporter assays revealed three novel enhancers-SRR18, SRR107, and SRR111-that, through the formation of chromatin loops, form a chromatin complex with the Sox2 promoter in ES cells. Using the CRISPR/ Cas9 system and F1 ES cells (Mus musculus 129 3 Mus castaneus), we generated heterozygous deletions of each enhancer region, revealing that only the distal cluster containing SRR107 and SRR111, located >100 kb downstream from Sox2, is required for cis-regulation of Sox2 in ES cells. Furthermore, homozygous deletion of this distal Sox2 control region (SCR) caused significant reduction in Sox2 mRNA and protein levels, loss of ES cell colony morphology, genome-wide changes in gene expression, and impaired neuroectodermal formation upon spontaneous differentiation to embryoid bodies. Together, these data identify a distal control region essential for Sox2 transcription in ES cells.

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“…The stochastic model predicts that SNPs found within cis-acting activators or repressors of XCI that are external to the Xist/Tsix locus can affect choice during XCI and could be within Xce candidate regions we have mapped. Moreover, there may be numerous times during development when Xce alleles function: before X-inactivation is triggered as alluded X chromosome analyses in ES cell (Mlynarczyk-Evans et al 2006;Monkhorst et al 2008), when X-chromosome pairing that occurs at the beginning stages of XCI (Bacher et al 2006;Xu et al 2006), or even during the short time after XCI is initiated when XCI is reversible (Wutz and Jaenisch 2000).…”

Section: Discussionmentioning

confidence: 99%

Nonrandom X Chromosome Inactivation Is Influenced by Multiple Regions on the Murine X Chromosome

et al. 2012

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During the development of female mammals, one of the two X chromosomes is inactivated, serving as a dosagecompensation mechanism to equalize the expression of X-linked genes in females and males. While the choice of which X chromosome to inactivate is normally random, X chromosome inactivation can be skewed in F1 hybrid mice, as determined by alleles at the X chromosome controlling element (Xce), a locus defined genetically by Cattanach over 40 years ago. Four Xce alleles have been defined in inbred mice in order of the tendency of the X chromosome to remain active: Xce a , Xce b , Xce c , Xce d . While the identity of the Xce locus remains unknown, previous efforts to map sequences responsible for the Xce effect in hybrid mice have localized the Xce to candidate regions that overlap the X chromosome inactivation center (Xic), which includes the Xist and Tsix genes. Here, we have intercrossed 129S1/SvImJ, which carries the Xce a allele, and Mus musculus castaneus EiJ, which carries the Xce c allele, to generate recombinant lines with single or double recombinant breakpoints near or within the Xce candidate region. In female progeny of 129S1/ SvImJ females mated to recombinant males, we have measured the X chromosome inactivation ratio using allele-specific expression assays of genes on the X chromosome. We have identified regions, both proximal and distal to Xist/Tsix, that contribute to the choice of which X chromosome to inactivate, indicating that multiple elements on the X chromosome contribute to the Xce. IN female mammals, either one of the two X chromosomes becomes inactivated during development of the embryo. This random form of X chromosome inactivation (XCI) was first proposed by Lyon (1961) to explain the mosaic pattern of X-linked phenotypes observed in coats of various mammals. XCI serves as a dosage-compensation mechanism to equalize the expression of most X-linked genes in females and males. The steps to random XCI during development of the embryonic lineage are thought to include counting of the number of X chromosomes and the choice of which will be active or inactive, followed by initiation, spreading and finally maintenance of the inactive state throughout development (Heard et al. 1997;Wutz 2011). While choice of which X to inactivate is known to be a primary event occurring early in development, when one X chromosome carries a detrimental mutation, preferential inactivation of the X chromosome with the mutation is typically observed (Morey and Avner 2010). This form of skewed XCI is exemplified in human cells and is most likely due to a secondary cell survival effect in choice (Puck and Willard 1998;Amos-Landgraf et al. 2006). In mice, random XCI is observed in homozygous females carrying X chromosomes from the same genetic background, whereas skewed XCI can be observed when females are heterozygous for X chromosomes from different backgrounds. In contrast to the situation observed in many human females, the process of this skewed XCI in mice is considered to be a primary event in t...

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X Chromosomes Alternate between Two States prior to Random X-Inactivation

Cited by 62 publications

References 39 publications

Long nuclear-retained non-coding RNAs and allele-specific higher-order chromatin organization at imprinted snoRNA gene arrays

Long nuclear-retained non-coding RNAs and allele-specific higher-order chromatin organization at imprinted snoRNA gene arrays

A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential

Nonrandom X Chromosome Inactivation Is Influenced by Multiple Regions on the Murine X Chromosome

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