Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]

Publication Date:
2018-12-04
Publisher:
Cold Spring Harbor Laboratory Press
Print ISSN:
0890-9369
Topics:
Biology
Published by:
http://www.cshlpress.com/
_version_ 1836399096291655680
autor Koerner, M. V., Fitz; Patrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A.
beschreibung Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt ( Tau ) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying MECP2 duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment.
citation_standardnr 6363998
datenlieferant ipn_articles
feed_id 1644
feed_publisher Cold Spring Harbor Laboratory Press
feed_publisher_url http://www.cshlpress.com/
insertion_date 2018-12-04
journalissn 0890-9369
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher Cold Spring Harbor Laboratory Press
quelle Genes & Development
relation http://genesdev.cshlp.org/cgi/content/short/32/23-24/1514?rss=1
search_space articles
shingle_author_1 Koerner, M. V., Fitz; Patrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A.
shingle_author_2 Koerner, M. V., Fitz; Patrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A.
shingle_author_3 Koerner, M. V., Fitz; Patrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A.
shingle_author_4 Koerner, M. V., Fitz; Patrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A.
shingle_catch_all_1 Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt ( Tau ) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying MECP2 duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment.
Koerner, M. V., Fitz; Patrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_catch_all_2 Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt ( Tau ) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying MECP2 duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment.
Koerner, M. V., Fitz; Patrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_catch_all_3 Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt ( Tau ) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying MECP2 duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment.
Koerner, M. V., Fitz; Patrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_catch_all_4 Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt ( Tau ) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying MECP2 duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment.
Koerner, M. V., Fitz; Patrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_title_1 Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
shingle_title_2 Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
shingle_title_3 Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
shingle_title_4 Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
timestamp 2025-06-30T23:37:32.640Z
titel Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
titel_suche Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
topic W
uid ipn_articles_6363998