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Introduction Congenital heart disease can result from defects in the epigenetic events driving cardiogenesis. Little is currently known about the chromatin structural changes that occur in cardiac progenitors. We are focusing on the role of NIPBL, a cohesin complex loading partner that plays a key role in the regulation of chromatin structure, during cardiogenesis. NIPBL mutations are associated with Cornelia de Lange Syndrome, characterised by an array of cardiac defects. Objective To characterise the role of Nipbl during cardiogenesis. Method We have used scRNAseq to analyse transcriptional alterations resulting from conditional knockout of NIPBL in early mouse embryos. Complementary ChIP-seq experiments are allowing us to characterise the epigenetic features of genes whose expression is altered as a result of NIPBL deficiency. Results scRNAseq has revealed that NIPBL deficiency leads to dramatic alterations in several transcripts, including members of the TGFbeta signalling pathway, within well-defined cardiac progenitor populations. These genes are found in regions of highly dynamic chromatin. Furthermore, specification of progenitor populations, including the lateral plate mesoderm, is affected. Conclusion The identification of genes whose expression is highly sensitive to NIPBL levels in cardiac progenitors has revealed potential therapeutic targets for congenital heart defects in Cornelia de Lange Syndrome patients. Also, this work provides novel insights into the role of NIPBL/cohesin during cardiogenesis. |
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