Requirement for Xist in X chromosome inactivation

Penny, Graeme D.; Kay, Graham F.; Sheardown, Steven A.; Rastan, Sohaila; Brockdorff, Neil

doi:10.1038/379131a0

Cited by 1,205 publications

(877 citation statements)

References 40 publications

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“…HeLa cells were maintained in DMEM supplemented with 10% FCS at 37°C and 5% CO 2 . The mouse ESC line PGK12.1, provided by N. Brockdorff, was cultured as previously described (Penny et al, 1996). …”

Section: Methodsmentioning

confidence: 99%

Non-canonical TAF complexes regulate active promoters in human embryonic stem cells

Maston

Zhu

Chamberlain

et al. 2012

eLife

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The general transcription factor TFIID comprises the TATA-box-binding protein (TBP) and approximately 14 TBP-associated factors (TAFs). Here we find, unexpectedly, that undifferentiated human embryonic stem cells (hESCs) contain only six TAFs (TAFs 2, 3, 5, 6, 7 and 11), whereas following differentiation all TAFs are expressed. Directed and global chromatin immunoprecipitation analyses reveal an unprecedented promoter occupancy pattern: most active genes are bound by only TAFs 3 and 5 along with TBP, whereas the remaining active genes are bound by TBP and all six hESC TAFs. Consistent with these results, hESCs contain a previously undescribed complex comprising TAFs 2, 6, 7, 11 and TBP. Altering the composition of hESC TAFs, either by depleting TAFs that are present or ectopically expressing TAFs that are absent, results in misregulated expression of pluripotency genes and induction of differentiation. Thus, the selective expression and use of TAFs underlies the ability of hESCs to self-renew.DOI: http://dx.doi.org/10.7554/eLife.00068.001

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Section: Methodsmentioning

confidence: 99%

Non-canonical TAF complexes regulate active promoters in human embryonic stem cells

Maston

Zhu

Chamberlain

et al. 2012

eLife

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“…In order to investigate the normality of XCI in cloned pigs, we selected five X-linked genes and one ubiquitous autosomal gene to compare their expression levels in major organs of cloned piglets and age-matched controls by quantitative real time RT-PCR. These genes are: 1) the untranslated X inactivation-specific transcript (XIST), which resides in the x-inactivation center (XIC) and serves as the master regulatory switch for X chromosome inactivation (Penny et al 1996); 2) the noncoding antisense mRNA of XIST, TSIX (the reserve spelling of XIST), which regulates both imprinted and random XCI through modification of chromatin structure in the mouse (Lee 2000;Sado et al 2005); 3) hypoxanthine guanine phosphoribosyltransferase 1 (HPRT1), a housekeeping gene on X-chromosome and its deficiency causes Lesch-Nyhan Syndrome in humans resulting symptoms such as gouty arthritis and kidney/bladder stones; 4) glucose-6-phosphate dehydrogenase (G6PD), an enzyme involved in the hexose monophosphate pathway and its deficiency in the embryonic tissues impairs the development of the placenta, causing the death of the embryo (Longo et al 2002); 5) V-raf murine sarcoma 3611 viral oncogene homolog 1 (ARAF1), a member of the raf proto-oncogene superfamily, which encodes cytoplasmic protein serine/threonine kinases and plays important roles in cell growth and development (Lee et al 1994); and 6) Alpha-1 type IV collagen (COL4A1), located on porcine Chromosome 11, when mutated causes vascular defects in mice followed by Porcencephaly in some mutants (Gould et al 2005). We found severe dysregulated expression of these genes in newborn deceased cloned piglets and moderate dysregulation in the surviving clones when compared to their respective age-matched controls.…”

Section: Introductionmentioning

confidence: 99%

Expression of X‐linked genes in deceased neonates and surviving cloned female piglets

Jiang

Lai

Samuel

et al. 2007

Molecular Reproduction Devel

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Animal cloning through somatic cell nuclear transfer is very inefficient, probably due to insufficient reprogramming of the donor nuclei, which in turn would cause the dysregulation of gene expression. X-Chromosome inactivation (XCI) is a multi-step epigenetic process utilized by mammals to achieve dosage compensation in females. Our aim was to determine if any dysregulation of X-linked genes, which would be indicative of unfaithful reprogramming of donor nuclei, was present in cloned pigs. Real time reverse transcription polymerase chain reaction (RT-PCR) was performed to quantify the transcript levels of five X-linked genes, XIST, TSIX, HPRT1, G6PD, ARAF1 and one autosomal gene, COL4A1 in major organs of neonatal deceased and surviving female cloned pigs and age-matched control pigs from conventional breeding. Aberrant expression level of these genes was prevalent in the neonatal deceased clones, while it was only moderate in cloned pigs that survived after birth. These results suggest a correlation between the viability of the clones and the normality of their gene expression and provide a possible explanation for the death of a large portion of cloned animals around birth.

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“…Xist is essential for the initiation of X-inactivation to occur in cis (Marahrens et al, 1997;Penny et al, 1996), and its expression is regulated by Tsix on the same chromosome in a negative fashion (Lee, 2000;Lee and Lu, 1999;Sado et al, 2001). The Xist/Tsix locus is probably one of the best-studied loci harboring a sense-antisense pair of transcripts, and study of this locus should allow us to obtain further insight into the molecular mechanisms underlying antisensemediated gene regulation, which appears to be rather common in a variety of systems.…”

Section: Introductionmentioning

confidence: 99%

Tsixdefective in splicing is competent to establishXistsilencing

2006

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Dosage differences of X-linked genes between male and female mammals are compensated for by a mechanism known as Xinactivation, and the noncoding Xist gene plays a crucial role in this process. The expression of Xist is regulated in cis by its noncoding antisense gene, Tsix, whose transcripts (though a fraction of them stay unspliced), are processed like common proteincoding RNAs. It has been suggested that certain classes of sense-antisense pairs of RNA are causally involved in not only gene regulation but also higher order chromatin structure in various organisms. In fact, recent studies demonstrated that Tsix modulates Xist expression through modification of the chromatin structure. It is still unknown, however, whether the RNA product is important for the function of Tsix or whether the antisense transcription is sufficient. To obtain insight into this issue, we eliminated the splicing products of Tsix in the mouse and explored the effects of this elimination on Tsix-mediated Xist silencing. To our surprise, the Xist locus was stably repressed on the X carrying the splicing-defective Tsix allele. Moreover, the repressive chromatin configuration was properly established at the Xist locus. These unexpected results indicate that the splicing products are dispensable for Tsix-mediated Xist silencing.

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Requirement for Xist in X chromosome inactivation

Cited by 1,205 publications

References 40 publications

Non-canonical TAF complexes regulate active promoters in human embryonic stem cells

Non-canonical TAF complexes regulate active promoters in human embryonic stem cells

Expression of X‐linked genes in deceased neonates and surviving cloned female piglets

Tsixdefective in splicing is competent to establishXistsilencing

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