Dicer regulates <it>Xist </it>promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a
<p>Abstract</p> <p>Background</p> <p>X chromosome inactivation is the mechanism used in mammals to achieve dosage compensation of X-linked genes in XX females relative to XY males. Chromosome silencing is triggered in <it>cis </it>by expression of the non-co...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2008-10-01
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| Series: | Epigenetics & Chromatin |
| Online Access: | http://www.epigeneticsandchromatin.com/content/1/1/2 |
| _version_ | 1818209047705288704 |
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| author | Nesterova Tatyana B Popova Bilyana C Cobb Bradley S Norton Sara Senner Claire E Tang Y Amy Spruce Thomas Rodriguez Tristan A Sado Takashi Merkenschlager Matthias Brockdorff Neil |
| author_facet | Nesterova Tatyana B Popova Bilyana C Cobb Bradley S Norton Sara Senner Claire E Tang Y Amy Spruce Thomas Rodriguez Tristan A Sado Takashi Merkenschlager Matthias Brockdorff Neil |
| author_sort | Nesterova Tatyana B |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>X chromosome inactivation is the mechanism used in mammals to achieve dosage compensation of X-linked genes in XX females relative to XY males. Chromosome silencing is triggered in <it>cis </it>by expression of the non-coding RNA <it>Xist</it>. As such, correct regulation of the <it>Xist </it>gene promoter is required to establish appropriate X chromosome activity both in males and females. Studies to date have demonstrated co-transcription of an antisense RNA <it>Tsix </it>and low-level sense transcription prior to onset of X inactivation. The balance of sense and antisense RNA is important in determining the probability that a given <it>Xist </it>allele will be expressed, termed the X inactivation choice, when X inactivation commences.</p> <p>Results</p> <p>Here we investigate further the mechanism of <it>Xist </it>promoter regulation. We demonstrate that both sense and antisense transcription modulate <it>Xist </it>promoter DNA methylation in undifferentiated embryonic stem (ES) cells, suggesting a possible mechanistic basis for influencing X chromosome choice. Given the involvement of sense and antisense RNAs in promoter methylation, we investigate a possible role for the RNA interference (RNAi) pathway. We show that the <it>Xist </it>promoter is hypomethylated in ES cells deficient for the essential RNAi enzyme Dicer, but that this effect is probably a secondary consequence of reduced levels of <it>de novo </it>DNA methyltransferases in these cells. Consistent with this we find that Dicer-deficient XY and XX embryos show appropriate <it>Xist </it>expression patterns, indicating that Xist gene regulation has not been perturbed.</p> <p>Conclusion</p> <p>We conclude that <it>Xist </it>promoter methylation prior to the onset of random X chromosome inactivation is influenced by relative levels of sense and antisense transcription but that this probably occurs independent of the RNAi pathway. We discuss the implications for this data in terms of understanding <it>Xist </it>gene regulation and X chromosome choice in random X chromosome inactivation.</p> |
| first_indexed | 2024-12-12T04:54:30Z |
| format | Article |
| id | doaj.art-a479f14878404bed94b7c75fa6bc2fb2 |
| institution | Directory Open Access Journal |
| issn | 1756-8935 |
| language | English |
| last_indexed | 2024-12-12T04:54:30Z |
| publishDate | 2008-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Epigenetics & Chromatin |
| spelling | doaj.art-a479f14878404bed94b7c75fa6bc2fb22022-12-22T00:37:24ZengBMCEpigenetics & Chromatin1756-89352008-10-0111210.1186/1756-8935-1-2Dicer regulates <it>Xist </it>promoter methylation in ES cells indirectly through transcriptional control of Dnmt3aNesterova Tatyana BPopova Bilyana CCobb Bradley SNorton SaraSenner Claire ETang Y AmySpruce ThomasRodriguez Tristan ASado TakashiMerkenschlager MatthiasBrockdorff Neil<p>Abstract</p> <p>Background</p> <p>X chromosome inactivation is the mechanism used in mammals to achieve dosage compensation of X-linked genes in XX females relative to XY males. Chromosome silencing is triggered in <it>cis </it>by expression of the non-coding RNA <it>Xist</it>. As such, correct regulation of the <it>Xist </it>gene promoter is required to establish appropriate X chromosome activity both in males and females. Studies to date have demonstrated co-transcription of an antisense RNA <it>Tsix </it>and low-level sense transcription prior to onset of X inactivation. The balance of sense and antisense RNA is important in determining the probability that a given <it>Xist </it>allele will be expressed, termed the X inactivation choice, when X inactivation commences.</p> <p>Results</p> <p>Here we investigate further the mechanism of <it>Xist </it>promoter regulation. We demonstrate that both sense and antisense transcription modulate <it>Xist </it>promoter DNA methylation in undifferentiated embryonic stem (ES) cells, suggesting a possible mechanistic basis for influencing X chromosome choice. Given the involvement of sense and antisense RNAs in promoter methylation, we investigate a possible role for the RNA interference (RNAi) pathway. We show that the <it>Xist </it>promoter is hypomethylated in ES cells deficient for the essential RNAi enzyme Dicer, but that this effect is probably a secondary consequence of reduced levels of <it>de novo </it>DNA methyltransferases in these cells. Consistent with this we find that Dicer-deficient XY and XX embryos show appropriate <it>Xist </it>expression patterns, indicating that Xist gene regulation has not been perturbed.</p> <p>Conclusion</p> <p>We conclude that <it>Xist </it>promoter methylation prior to the onset of random X chromosome inactivation is influenced by relative levels of sense and antisense transcription but that this probably occurs independent of the RNAi pathway. We discuss the implications for this data in terms of understanding <it>Xist </it>gene regulation and X chromosome choice in random X chromosome inactivation.</p>http://www.epigeneticsandchromatin.com/content/1/1/2 |
| spellingShingle | Nesterova Tatyana B Popova Bilyana C Cobb Bradley S Norton Sara Senner Claire E Tang Y Amy Spruce Thomas Rodriguez Tristan A Sado Takashi Merkenschlager Matthias Brockdorff Neil Dicer regulates <it>Xist </it>promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a Epigenetics & Chromatin |
| title | Dicer regulates <it>Xist </it>promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a |
| title_full | Dicer regulates <it>Xist </it>promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a |
| title_fullStr | Dicer regulates <it>Xist </it>promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a |
| title_full_unstemmed | Dicer regulates <it>Xist </it>promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a |
| title_short | Dicer regulates <it>Xist </it>promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a |
| title_sort | dicer regulates it xist it promoter methylation in es cells indirectly through transcriptional control of dnmt3a |
| url | http://www.epigeneticsandchromatin.com/content/1/1/2 |
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