ABSTRACT
22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion syndrome. Congenital heart defects are prevalent in 22q11.2DS but the etiology is still poorly understood. In this study, we aimed to gain mechanistic insights into the heart defects that result from 22q11.2 deletion, with a focus on Slc25a1, which is located in the deletion segment. Whereas global knockout of Slc25a1 in mice produced a variety of heart malformations, cardiac deletion of Slc25a1 had little effect on heart development. We then found that trophoblast-specific Slc25a1 deletion recapitulated heart anomalies in the global knockout mice. Further study identified SLC25A1 as a regulator of trophoblast and placental development through modulation of histone H3K27 acetylation at the promoters and enhancers of key genes involved in trophoblast differentiation. Finally, administration of recombinant human pregnancy-specific glycoprotein 1 (PSG1), a trophoblast-derived secretory glycoprotein, partially corrected placental and embryonic heart defects. This study defines the role of SLC25A1 in heart development by regulating placental development, and provides new insights to understand the etiology of 22q11.2DS.
Footnotes
Author contributions
Conceptualization: Z.Y.; Formal analysis: Z.Y.; Funding acquisition: M.S., Z.Y.; Investigation: W.F., Z.L., X.H., X.W.; Methodology: W.F., Z.Y.; Project administration: Z.Y.; Writing – original draft: W.F.; Writing – review & editing: Z.Y.
Funding
This work was supported by grants from the National Key Research and Development Program of China (2019YFA0801601) and from the National Natural Science Foundation of China (31930029 and 91854111) to Z.Y.
Data availability
RNA-seq and CUT&Tag data have been deposited in the Sequence Read Archive (SRA) database under accession numbers PRJNA1132003 and PRJNA1142768. The scRNA-seq data reported in this paper are available at the NCBI Gene Expression Omnibus (GEO) under accession number GSE273446.
The people behind the papers
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