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Published on: January 14, 2016
In cortical neurons HDAC3 activity suppresses RD4-dependent SMRT export
Francesc X Soriano1, Giles E Hardingham
1Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
Plos One
|June 23, 2011
Summary
The transcriptional corepressor SMRT requires histone deacetylase 3 (HDAC3) activity to remain in neuronal nuclei. HDAC inhibitors trigger SMRT export, involving its RD4 domain, revealing how these drugs reorganize corepressor complexes.
Area of Science:
- Neuroscience
- Molecular Biology
- Epigenetics
Background:
- The transcriptional corepressor SMRT (silencing mediator for retinoic acid receptor D) plays a key role in neuronal function.
- SMRT interacts with histone deacetylases (HDACs), including HDAC3, and influences neuroprotective and neurogenic pathways.
- Previous work indicated that inhibiting class I/II HDACs causes SMRT to move from the nucleus to the cytoplasm.
Purpose of the Study:
- To identify the specific HDACs and SMRT regions involved in nuclear localization and HDAC inhibitor-induced nuclear export.
- To elucidate the mechanism by which HDAC inhibitors affect SMRT localization in neurons.
Main Methods:
- Utilized rat cortical neurons treated with various HDAC inhibitors (TSA, valproate, apicidin) and employed knockdown strategies for HDAC3.
- Investigated SMRT localization through subcellular fractionation and microscopy.
- Generated SMRT mutants, including deletions and point mutations in its deacetylation activation domain (DAD) and repression domain-4 (RD4), to assess their role in nuclear anchoring and export.
Main Results:
- HDAC3 activity is necessary for maintaining SMRT in the neuronal nucleus, as HDAC3 knockdown and inhibition (using apicidin) induced SMRT export.
- Inactivation of SMRT's DAD region led to partial cytoplasmic redistribution, suggesting its role in nuclear retention.
- Deletion of SMRT's RD4 domain significantly impaired TSA- and valproate-induced nuclear export, and overexpression of the RD4 region suppressed this export, implicating RD4 in mediating export.
Conclusions:
- HDAC3 activity maintains SMRT nuclear localization, potentially by suppressing the function or recruitment of factors associated with SMRT's RD4 domain.
- HDAC inhibitors can induce SMRT nuclear export via its RD4 domain, demonstrating that these drugs reorganize corepressor complex localization.
- These findings provide insights into the dynamic regulation of SMRT and corepressor complexes by HDAC activity in neurons.
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