Histone deacetylase 4 deletion broadly affects cardiac epigenetic repression and regulates transcriptional susceptibility via H3K9 methylation
Histone deacetylase 4 (HDAC4) is a member of class IIa histone deacetylases (class IIa HDACs) and is believed to possess a low intrinsic deacetylase activity. However, HDAC4 sufficiently represses distinct transcription factors (TFs) such as the myocyte enhancer factor 2 (MEF2). Transcriptional repr...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
4 September 2021
|
| In: |
Journal of molecular and cellular cardiology
Year: 2022, Volume: 162, Pages: 119-129 |
| ISSN: | 1095-8584 |
| DOI: | 10.1016/j.yjmcc.2021.09.001 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.yjmcc.2021.09.001 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0022282821001735 
|
| Author Notes: | Daniel Finke, Leonard M. Schanze, Friederike Schreiter, Michael M. Kreußer, Hugo A. Katus, Johannes Backs, Lorenz H. Lehmann |
| Summary: | Histone deacetylase 4 (HDAC4) is a member of class IIa histone deacetylases (class IIa HDACs) and is believed to possess a low intrinsic deacetylase activity. However, HDAC4 sufficiently represses distinct transcription factors (TFs) such as the myocyte enhancer factor 2 (MEF2). Transcriptional repression by HDAC4 has been suggested to be mediated by the recruitment of other chromatin-modifying enzymes, such as methyltransferases or class I histone deacetylases. However, this concept has not been investigated by an unbiased approach. Therefore, we studied the histone modifications H3K4me3, H3K9ac, H3K27ac, H3K9me2 and H3K27me3 in a genome-wide approach using HDAC4-deficient cardiomyocytes. We identified a general epigenetic shift from a ‘repressive’ to an ‘active’ status, characterized by an increase of H3K4me3, H3K9ac and H3K27ac and a decrease of H3K9me2 and H3K27me3. In HDAC4-deficient cardiomyocytes, MEF2 binding sites were considerably overrepresented in upregulated promoter regions of H3K9ac and H3K4me3. For example, we identified the promoter of Adprhl1 as a new genomic target of HDAC4 and MEF2. Overexpression of HDAC4 in cardiomyocytes was able to repress the transcription of the Adprhl1 promoter in the presence of the methyltransferase SUV39H1. On a genome-wide level, the decrease of H3K9 methylation did not change baseline expression but was associated with exercise-induced gene expression. We conclude that HDAC4, on the one hand, associates with activating histone modifications, such as H3K4me3 and H3K9ac. A functional consequence, on the other hand, requires an indirect regulation of H3K9me2. H3K9 hypomethylation in HDAC4 target genes (‘first hit’) plus a ‘second hit’ (e.g., exercise) determines the transcriptional response. |
|---|---|
| Item Description: | Gesehen am 26.11.2021 |
| Physical Description: | Online Resource |
| ISSN: | 1095-8584 |
| DOI: | 10.1016/j.yjmcc.2021.09.001 |