Recently, in a research report published in the international journal Proceedings of the National Academy of Sciences, scientists from the University of Alabama at Birmingham and other institutions have clarified the cause and molecular mechanism of the serious birth defect called CHARGE syndrome (CHARGE joint deformity, nostril atresia deformity) through research. In the article, the researchers successfully inactivated the CHD7 gene in mouse embryonic neural crest cells, and then tracked how the inactivation of the CHD7 gene in the developing cardiac neural crest cells induced serious defects in the right ventricular outflow tract and large arteries of the heart, and lead to perinatal death of the fetus. Heart defects and other birth defects in embryos are similar to human CHARGE syndrome defects. Currently, known CHD7 mutations can induce approximately 70% of human CHARGE syndrome.
In this study, the researchers clarified a long-standing controversy in the scientific community. Previously, some researchers tried to change the function of CHD7 in neural crest cells, but they could not induce heart defects in various mouse models. The researchers improved on this with better molecular scissors to remove key parts of the CHD7 gene to inactivate it. Researchers unexpectedly discovered that in addition to the established ATP-dependent chromatin remodeling activity, CHD7 also has a new type of epigenetic function; chromatin remodeling factors such as CHD7 can use ATP to remodel chromatin. This will allow selective gene expression to grow into a complex embryo containing at least 200 different types of cells (these cells all come from the same DNA genome, but they will use different genetic procedures for differentiation). During the process, turning off or turning on specific gene groups is the basis of embryonic development.
In addition to the chromatin remodeling activity, the researchers also found that CHD7 can also recruit histone-modifying enzymes in an ATP-dependent manner, thereby targeting, promoting and enhancing the activity of sites on the genome. Researcher Jiao said, “we found that CHD7 can also directly recruit H3K4 methyltransferase to act on the targeting elements. This dual activity of CHD7 may represent an effective mechanism to coordinate the remodeling of nucleosomes and the methylation modification of H3K4 at these targeted sites. The interaction between CHD7 nucleosome remodelers and histone methylation modification machinery may form a positive feedback loop to stabilize the epigenetic state of the targeting element.”
In addition to clarifying the important cellular intelligence role of CHD7 in regulating the development of cardiac neural crest cells, the researchers also stated that a single point mutation in the CHD7 gene is sufficient to induce serious developmental defects and embryonic lethal effects in mammals. The researchers also used transcriptomics analysis to reveal that CHD7 can regulate the expression of a network of genes critical to the development of cardiac neural crest cells. Then the researchers conducted a screening of protein-protein interactions and found that CHD7 can directly interact with a variety of dysplasia mutant proteins, one of which is WDR5, which is the H3K4 methyltransferase complex Core ingredient. The interaction between CHD7 and WDR5 also illustrates the ability of CHD7 to recruit histone-modifying enzymes to target promoter or enhancer sites on the genome. The researchers said that the secret of the CHD7 protein interaction group indicates that CHD7 may be involved in a wider range of physiological processes and the occurrence of human diseases, which may be more than previously expected by researchers.
Researcher Jiao said, “It is important that we provide a molecular framework to screen candidate members to investigate the function of CHD7 and the molecular etiology of CHD7-related diseases and phenotypes. The discovery of two different functions of CHD7 may have important clinical significance and value.” Finally, the researchers said that research data shows that patients with premature stop codons and patients with missense mutations may show different molecular changes, therefore, these patients may need individualized therapeutic intervention to improve their condition.