Reactivation of a silenced <it>H19</it> gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation
<p>Abstract</p> <p>Background</p> <p>The active copy of the imprinted gene <it>H19</it> is turned off by inappropriate methylation in several pediatric tumors including Wilms' Tumour and embryonal rhabdomyosarcoma. <it>H19</it> controls in &...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2002-07-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/1/1/2 |
| _version_ | 1811312144406282240 |
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| author | Bestor Timothy H Tycko Benjamin Lynch Catherine A Walsh Colum P |
| author_facet | Bestor Timothy H Tycko Benjamin Lynch Catherine A Walsh Colum P |
| author_sort | Bestor Timothy H |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>The active copy of the imprinted gene <it>H19</it> is turned off by inappropriate methylation in several pediatric tumors including Wilms' Tumour and embryonal rhabdomyosarcoma. <it>H19</it> controls in <it>cis</it> the linked <it>Insulin-like Growth Factor 2</it> (<it>IGF2</it>) gene, encoding an important growth factor. Recent work has suggested that methylation of a gene may lead to deacetylation of its associated histones and that silenced genes can be reactivated by increasing histone acetylation levels.</p> <p>Results</p> <p>Treatment of a rhabdomyosarcoma cell line which has a silent, methylated <it>H19</it> gene with histone deacetylase (HDAC) inhibitors under conditions which gave maximal hyperacetylation of histone 4, both globally and at the <it>H19</it> gene itself could not reactivate <it>H19</it> or affect the active <it>Insulin-like Growth Factor 2</it> (<it>IGF2</it>) gene, but caused clear up-regulation of the <it>Tissue-type Plasminogen Activator</it> (<it>TPA</it>) gene, a non-imprinted gene known to respond to changes in histone acetylation. In contrast, mild treatment of the cells with the methylation inhibitor 5-AzaC-2'-deoxycytidine (AzaC) on its own was able to reactivate <it>H19</it>. Combining AzaC treatment with HDAC inhibitors gave a reduced rather than enhanced reactivation. These findings were confirmed in mouse primary liver and kidney explants which maintain normal imprinting, where we also found that the silent <it>Igf2</it> gene could not be reactivated by HDAC inhibitors.</p> <p>Conclusion</p> <p>These results suggest that DNA methylation rather than histone acetylation is the primary determinant of silencing of <it>H19</it> in rhabdomyosarcoma.</p> |
| first_indexed | 2024-04-13T10:31:05Z |
| format | Article |
| id | doaj.art-eeb56f221fbc4a4c9ec2c27dea1045a8 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-04-13T10:31:05Z |
| publishDate | 2002-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-eeb56f221fbc4a4c9ec2c27dea1045a82022-12-22T02:50:11ZengBMCMolecular Cancer1476-45982002-07-0111210.1186/1476-4598-1-2Reactivation of a silenced <it>H19</it> gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylationBestor Timothy HTycko BenjaminLynch Catherine AWalsh Colum P<p>Abstract</p> <p>Background</p> <p>The active copy of the imprinted gene <it>H19</it> is turned off by inappropriate methylation in several pediatric tumors including Wilms' Tumour and embryonal rhabdomyosarcoma. <it>H19</it> controls in <it>cis</it> the linked <it>Insulin-like Growth Factor 2</it> (<it>IGF2</it>) gene, encoding an important growth factor. Recent work has suggested that methylation of a gene may lead to deacetylation of its associated histones and that silenced genes can be reactivated by increasing histone acetylation levels.</p> <p>Results</p> <p>Treatment of a rhabdomyosarcoma cell line which has a silent, methylated <it>H19</it> gene with histone deacetylase (HDAC) inhibitors under conditions which gave maximal hyperacetylation of histone 4, both globally and at the <it>H19</it> gene itself could not reactivate <it>H19</it> or affect the active <it>Insulin-like Growth Factor 2</it> (<it>IGF2</it>) gene, but caused clear up-regulation of the <it>Tissue-type Plasminogen Activator</it> (<it>TPA</it>) gene, a non-imprinted gene known to respond to changes in histone acetylation. In contrast, mild treatment of the cells with the methylation inhibitor 5-AzaC-2'-deoxycytidine (AzaC) on its own was able to reactivate <it>H19</it>. Combining AzaC treatment with HDAC inhibitors gave a reduced rather than enhanced reactivation. These findings were confirmed in mouse primary liver and kidney explants which maintain normal imprinting, where we also found that the silent <it>Igf2</it> gene could not be reactivated by HDAC inhibitors.</p> <p>Conclusion</p> <p>These results suggest that DNA methylation rather than histone acetylation is the primary determinant of silencing of <it>H19</it> in rhabdomyosarcoma.</p>http://www.molecular-cancer.com/content/1/1/2 |
| spellingShingle | Bestor Timothy H Tycko Benjamin Lynch Catherine A Walsh Colum P Reactivation of a silenced <it>H19</it> gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation Molecular Cancer |
| title | Reactivation of a silenced <it>H19</it> gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation |
| title_full | Reactivation of a silenced <it>H19</it> gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation |
| title_fullStr | Reactivation of a silenced <it>H19</it> gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation |
| title_full_unstemmed | Reactivation of a silenced <it>H19</it> gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation |
| title_short | Reactivation of a silenced <it>H19</it> gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation |
| title_sort | reactivation of a silenced it h19 it gene in human rhabdomyosarcoma by demethylation of dna but not by histone hyperacetylation |
| url | http://www.molecular-cancer.com/content/1/1/2 |
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