Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression.
Adult blood cell production or definitive hematopoiesis requires the transcription factor c-Myb. The closely related KAT3 histone acetyltransferases CBP (CREBBP) and p300 (EP300) bind c-Myb through their KIX domains and mice homozygous for a p300 KIX domain mutation exhibit multiple blood defects. P...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3858336?pdf=render |
| _version_ | 1818940711969488896 |
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| author | Lawryn H Kasper Tomofusa Fukuyama Stephanie Lerach Yunchao Chang Wu Xu Song Wu Kelli L Boyd Paul K Brindle |
| author_facet | Lawryn H Kasper Tomofusa Fukuyama Stephanie Lerach Yunchao Chang Wu Xu Song Wu Kelli L Boyd Paul K Brindle |
| author_sort | Lawryn H Kasper |
| collection | DOAJ |
| description | Adult blood cell production or definitive hematopoiesis requires the transcription factor c-Myb. The closely related KAT3 histone acetyltransferases CBP (CREBBP) and p300 (EP300) bind c-Myb through their KIX domains and mice homozygous for a p300 KIX domain mutation exhibit multiple blood defects. Perplexingly, mice homozygous for the same KIX domain mutation in CBP have normal blood. Here we test the hypothesis that the CBP KIX domain contributes subordinately to hematopoiesis via a genetic interaction with c-Myb. We assessed hematopoiesis in mice bearing compound mutations of c-Myb and/or the KIX domains of CBP and p300, and measured the effect of KIX domain mutations on c-Myb-dependent gene expression. We found that in the context of a p300 KIX mutation, the CBP KIX domain mutation affects platelets, B cells, T cells, and red cells. Gene interaction (epistasis) analysis provides mechanistic evidence that blood defects in KIX mutant mice are consistent with reduced c-Myb and KIX interaction. Lastly, we demonstrated that the CBP and p300 KIX domains contribute to both c-Myb-dependent gene activation and repression. Together these results suggest that the KIX domains of CBP, and especially p300, are principal mediators of c-Myb-dependent gene activation and repression that is required for definitive hematopoiesis. |
| first_indexed | 2024-12-20T06:44:00Z |
| format | Article |
| id | doaj.art-2c85f4f85a3f48deb1b5925a3920a8f0 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T06:44:00Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2c85f4f85a3f48deb1b5925a3920a8f02022-12-21T19:49:46ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01812e8268410.1371/journal.pone.0082684Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression.Lawryn H KasperTomofusa FukuyamaStephanie LerachYunchao ChangWu XuSong WuKelli L BoydPaul K BrindleAdult blood cell production or definitive hematopoiesis requires the transcription factor c-Myb. The closely related KAT3 histone acetyltransferases CBP (CREBBP) and p300 (EP300) bind c-Myb through their KIX domains and mice homozygous for a p300 KIX domain mutation exhibit multiple blood defects. Perplexingly, mice homozygous for the same KIX domain mutation in CBP have normal blood. Here we test the hypothesis that the CBP KIX domain contributes subordinately to hematopoiesis via a genetic interaction with c-Myb. We assessed hematopoiesis in mice bearing compound mutations of c-Myb and/or the KIX domains of CBP and p300, and measured the effect of KIX domain mutations on c-Myb-dependent gene expression. We found that in the context of a p300 KIX mutation, the CBP KIX domain mutation affects platelets, B cells, T cells, and red cells. Gene interaction (epistasis) analysis provides mechanistic evidence that blood defects in KIX mutant mice are consistent with reduced c-Myb and KIX interaction. Lastly, we demonstrated that the CBP and p300 KIX domains contribute to both c-Myb-dependent gene activation and repression. Together these results suggest that the KIX domains of CBP, and especially p300, are principal mediators of c-Myb-dependent gene activation and repression that is required for definitive hematopoiesis.http://europepmc.org/articles/PMC3858336?pdf=render |
| spellingShingle | Lawryn H Kasper Tomofusa Fukuyama Stephanie Lerach Yunchao Chang Wu Xu Song Wu Kelli L Boyd Paul K Brindle Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression. PLoS ONE |
| title | Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression. |
| title_full | Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression. |
| title_fullStr | Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression. |
| title_full_unstemmed | Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression. |
| title_short | Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression. |
| title_sort | genetic interaction between mutations in c myb and the kix domains of cbp and p300 affects multiple blood cell lineages and influences both gene activation and repression |
| url | http://europepmc.org/articles/PMC3858336?pdf=render |
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