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Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4
H D Youn1, C M Grozinger, J O Liu
1Center for Cancer Research, Department of Chemistry and Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Abstract:
The myocyte enhancer factor 2 (MEF2) consists of a family of transcription factors that play important roles in a number of physiological processes from muscle cell differentiation to neuronal survival and T cell apoptosis. MEF2 has been reported to be associated with several distinct repressors including Cabin1(cain), MEF2-interacting transcriptional repressor (MITR), and HDAC4. It has been previously shown that Cabin1 is associated with MEF2 in a calcium-sensitive manner; activated calmodulin binds to Cabin1 and releases it from MEF2. However, it was not known whether the binding of HDAC4 and MITR to MEF2 is also regulated by calcium. We report that HDAC4 and MITR contain calmodulin-binding domains that overlap with their MEF2-binding domains. Binding of calmodulin to HDAC4 leads to its dissociation from MEF2, relieving MEF2 from the transcriptional repression by HDAC4. Together, HDAC4, MITR, and Cabin1 constitute a family of calcium-sensitive transcriptional repressors of MEF2.
Insights
Calcium signaling regulates myocyte enhancer factor 2 (MEF2) activity. Calmodulin binding to repressors HDAC4 and MITR releases MEF2, revealing a family of calcium-sensitive MEF2 repressors involved in cellular processes.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Transcription Factor Regulation
Background:
- Myocyte enhancer factor 2 (MEF2) transcription factors are crucial for cellular differentiation and survival.
- MEF2 activity is regulated by associated proteins, including repressors like Cabin1, MITR, and HDAC4.
- Cabin1's interaction with MEF2 is known to be calcium-sensitive.
Purpose of the Study:
- To investigate whether calcium also regulates the binding of HDAC4 and MITR to MEF2.
- To determine if HDAC4 and MITR possess calcium-sensitive regulatory mechanisms similar to Cabin1.
Main Methods:
- Biochemical assays to analyze protein-protein interactions.
- Identification and characterization of calmodulin-binding domains within HDAC4 and MITR.
- Assessing the effect of calmodulin binding on the MEF2-repressor complex.
Main Results:
- HDAC4 and MITR possess calmodulin-binding domains that overlap with their MEF2-binding domains.
- Calmodulin binding to HDAC4 induces its dissociation from MEF2.
- This dissociation relieves MEF2 from transcriptional repression mediated by HDAC4.
Conclusions:
- HDAC4 and MITR function as calcium-sensitive repressors of MEF2.
- HDAC4, MITR, and Cabin1 collectively form a family of calcium-regulated MEF2 transcriptional repressors.
- Calcium signaling plays a key role in modulating MEF2 transcriptional activity through these repressors.