Abstract
TBX5 is a T-box family transcription factor that regulates heart and forelimb development in vertebrates and functional deficiencies in this protein result in Holt-Oram syndrome. Recently, we have shown that acetylation of TBX5 potentiates its activity and is important for heart and limb development. Here we report that class II histone deacetylases HDAC4 and HDAC5 associate with TBX5 and repress its role in cardiac gene transcription. Both HDAC4 and HDAC5 deacetylate TBX5, which promotes its relocation to the cytoplasm and HDAC4 antagonizes the physical association and functional cooperation between TBX5 and MEF2C. We also show that protein kinase D1 (PRKD1) relieves the HDAC4/5-mediated repression of TBX5. Thus, this study reveals a novel interaction of HDAC4/5 and PRKD1 in the regulation of TBX5 transcriptional activity.
Highlights
TBX5 is a T-box family transcription factor that regulates heart and forelimb development in vertebrates and functional deficiencies in this protein result in Holt-Oram syndrome
The functional cooperation between these factors is crucial for proper heart development, and mutations that disrupt such association often lead to congenital heart diseases (CHDs)
Our pull-down assays suggest that TBX5 associates with both class I (HDAC1, 2 and 3) and class II Histone deacetylases (HDACs) (HDAC4 and 5)
Summary
TBX5 is a T-box family transcription factor that regulates heart and forelimb development in vertebrates and functional deficiencies in this protein result in Holt-Oram syndrome. We report that class II histone deacetylases HDAC4 and HDAC5 associate with TBX5 and repress its role in cardiac gene transcription. Both HDAC4 and HDAC5 deacetylate TBX5, which promotes its relocation to the cytoplasm and HDAC4 antagonizes the physical association and functional cooperation between TBX5 and MEF2C. Class II HDACs are highly similar to yeast HDA1 (histone deacetylase-A 1) and suppress heart growth[10]. They are abundantly expressed in the heart, brain and skeletal muscles[11] and are signal responsive repressors of cardiac hypertrophy[10]. Acetylation potentiates the transcriptional activity of TBX517 and histone deacetylases are key players in heart development and cardiac hypertrophy[10]. These studies suggest the TBX5-mediated gene regulatory pathway is linked to a signal-mediated protein kinase via PRKD1
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