PUBLICATION
The Gridlock transcriptional repressor impedes vertebrate heart regeneration by restricting expression of lysine methyltransferase
- Authors
- She, P., Zhang, H., Peng, X., Sun, J., Gao, B., Zhou, Y., Zhu, X., Hu, X., Lai, K.S., Wong, J., Zhou, B., Wang, L., Zhong, T.P.
- ID
- ZDB-PUB-201002-202
- Date
- 2020
- Source
- Development (Cambridge, England) 147(18): (Journal)
- Registered Authors
- Zhong, Tao P.
- Keywords
- Cardiomyocyte proliferation, Grl, Heart regeneration, Hey2, Lysine methyltransferase, Zebrafish
- Datasets
- GEO:GSE129499
- MeSH Terms
-
- Methyltransferases/genetics*
- Animals, Newborn
- Myocytes, Cardiac/metabolism
- Regeneration/genetics*
- Animals
- Signal Transduction/genetics
- Heart/physiology*
- Vertebrates/genetics*
- Basic Helix-Loop-Helix Transcription Factors/genetics*
- Myocardium/metabolism
- Lysine/genetics*
- Zebrafish Proteins/genetics*
- Cell Differentiation/genetics
- Zebrafish/genetics
- Phosphorylation/genetics
- Transcription, Genetic/genetics*
- Cell Proliferation/genetics
- STAT3 Transcription Factor/genetics
- PubMed
- 32988975 Full text @ Development
Citation
She, P., Zhang, H., Peng, X., Sun, J., Gao, B., Zhou, Y., Zhu, X., Hu, X., Lai, K.S., Wong, J., Zhou, B., Wang, L., Zhong, T.P. (2020) The Gridlock transcriptional repressor impedes vertebrate heart regeneration by restricting expression of lysine methyltransferase. Development (Cambridge, England). 147(18):.
Abstract
Teleost zebrafish and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). Although many mitogenic signals that stimulate zebrafish heart regeneration have been identified, transcriptional programs that restrain injury-induced CM renewal are incompletely understood. Here, we report that mutations in gridlock (grl; also known as hey2), encoding a Hairy-related basic helix-loop-helix transcriptional repressor, enhance CM proliferation and reduce fibrosis following damage. In contrast, myocardial grl induction blunts CM dedifferentiation and regenerative responses to heart injury. RNA sequencing analyses uncover Smyd2 lysine methyltransferase (KMT) as a key transcriptional target repressed by Grl. Reduction in Grl protein levels triggered by injury induces smyd2 expression at the wound myocardium, enhancing CM proliferation. We show that Smyd2 functions as a methyltransferase and modulates the Stat3 methylation and phosphorylation activity. Inhibition of the KMT activity of Smyd2 reduces phosphorylated Stat3 at cardiac wounds, suppressing the elevated CM proliferation in injured grl mutant hearts. Our findings establish an injury-specific transcriptional repression program in governing CM renewal during heart regeneration, providing a potential strategy whereby silencing Grl repression at local regions might empower regeneration capacity to the injured mammalian heart.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping