CHD4 and SMYD1 repress common transcriptional programs in the developing heart

Development. 2024 Apr 15;151(8):dev202505. doi: 10.1242/dev.202505. Epub 2024 May 3.

Abstract

Regulation of chromatin states is essential for proper temporal and spatial gene expression. Chromatin states are modulated by remodeling complexes composed of components that have enzymatic activities. CHD4 is the catalytic core of the nucleosome remodeling and deacetylase (NuRD) complex, which represses gene transcription. However, it remains to be determined how CHD4, a ubiquitous enzyme that remodels chromatin structure, functions in cardiomyocytes to maintain heart development. In particular, whether other proteins besides the NuRD components interact with CHD4 in the heart is controversial. Using quantitative proteomics, we identified that CHD4 interacts with SMYD1, a striated muscle-restricted histone methyltransferase that is essential for cardiomyocyte differentiation and cardiac morphogenesis. Comprehensive transcriptomic and chromatin accessibility studies of Smyd1 and Chd4 null embryonic mouse hearts revealed that SMYD1 and CHD4 repress a group of common genes and pathways involved in glycolysis, response to hypoxia, and angiogenesis. Our study reveals a mechanism by which CHD4 functions during heart development, and a previously uncharacterized mechanism regarding how SMYD1 represses cardiac transcription in the developing heart.

Keywords: CHD4; Chromatin accessibility; Mouse; SMYD1; Transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Chromatin / metabolism
  • DNA Helicases*
  • DNA-Binding Proteins*
  • Gene Expression Regulation, Developmental*
  • Glycolysis / genetics
  • Heart* / embryology
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex* / genetics
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex* / metabolism
  • Mice
  • Mice, Knockout
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Myocytes, Cardiac* / metabolism
  • Proteomics
  • Transcription Factors*
  • Transcription, Genetic

Substances

  • Chromatin
  • DNA Helicases
  • DNA-Binding Proteins
  • Histone-Lysine N-Methyltransferase
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • Mi-2beta protein, mouse
  • Muscle Proteins
  • Smyd1 protein, mouse
  • Transcription Factors
  • CHD4 protein, human