SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome.
Expansion of the CGG.CCG-repeat tract in the 5' UTR of the FMR1 gene to >200 repeats leads to heterochromatinization of the promoter and gene silencing. This results in Fragile X syndrome (FXS), the most common heritable form of mental retardation. The mechanism of gene silencing is unknown....
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-03-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2265469?pdf=render |
| _version_ | 1819171497593274368 |
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| author | Rea Biacsi Daman Kumari Karen Usdin |
| author_facet | Rea Biacsi Daman Kumari Karen Usdin |
| author_sort | Rea Biacsi |
| collection | DOAJ |
| description | Expansion of the CGG.CCG-repeat tract in the 5' UTR of the FMR1 gene to >200 repeats leads to heterochromatinization of the promoter and gene silencing. This results in Fragile X syndrome (FXS), the most common heritable form of mental retardation. The mechanism of gene silencing is unknown. We report here that a Class III histone deacetylase, SIRT1, plays an important role in this silencing process and show that the inhibition of this enzyme produces significant gene reactivation. This contrasts with the much smaller effect of inhibitors like trichostatin A (TSA) that inhibit Class I, II and IV histone deacetylases. Reactivation of silenced FMR1 alleles was accompanied by an increase in histone H3 lysine 9 acetylation as well as an increase in the amount of histone H4 that is acetylated at lysine 16 (H4K16) by the histone acetyltransferase, hMOF. DNA methylation, on the other hand, is unaffected. We also demonstrate that deacetylation of H4K16 is a key downstream consequence of DNA methylation. However, since DNA methylation inhibitors require DNA replication in order to be effective, SIRT1 inhibitors may be more useful for FMR1 gene reactivation in post-mitotic cells like neurons where the effect of the gene silencing is most obvious. |
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| format | Article |
| id | doaj.art-8500b6d849ac43399b6e245f549073f1 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-22T19:52:14Z |
| publishDate | 2008-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-8500b6d849ac43399b6e245f549073f12022-12-21T18:14:31ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042008-03-0143e100001710.1371/journal.pgen.1000017SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome.Rea BiacsiDaman KumariKaren UsdinExpansion of the CGG.CCG-repeat tract in the 5' UTR of the FMR1 gene to >200 repeats leads to heterochromatinization of the promoter and gene silencing. This results in Fragile X syndrome (FXS), the most common heritable form of mental retardation. The mechanism of gene silencing is unknown. We report here that a Class III histone deacetylase, SIRT1, plays an important role in this silencing process and show that the inhibition of this enzyme produces significant gene reactivation. This contrasts with the much smaller effect of inhibitors like trichostatin A (TSA) that inhibit Class I, II and IV histone deacetylases. Reactivation of silenced FMR1 alleles was accompanied by an increase in histone H3 lysine 9 acetylation as well as an increase in the amount of histone H4 that is acetylated at lysine 16 (H4K16) by the histone acetyltransferase, hMOF. DNA methylation, on the other hand, is unaffected. We also demonstrate that deacetylation of H4K16 is a key downstream consequence of DNA methylation. However, since DNA methylation inhibitors require DNA replication in order to be effective, SIRT1 inhibitors may be more useful for FMR1 gene reactivation in post-mitotic cells like neurons where the effect of the gene silencing is most obvious.http://europepmc.org/articles/PMC2265469?pdf=render |
| spellingShingle | Rea Biacsi Daman Kumari Karen Usdin SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome. PLoS Genetics |
| title | SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome. |
| title_full | SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome. |
| title_fullStr | SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome. |
| title_full_unstemmed | SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome. |
| title_short | SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome. |
| title_sort | sirt1 inhibition alleviates gene silencing in fragile x mental retardation syndrome |
| url | http://europepmc.org/articles/PMC2265469?pdf=render |
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