Genetic Networks Governing Heart Development

Sequence mutations in cardiac CREs are associated with congenital heart disease.

“The function of most CREs is unknown; however, there is mounting evidence that sequence mutations in cardiac CREs are associated with congenital heart disease [2, 3].”

A strong cardiac cis-regulatory signature was observed in Category I with enrichment of binding sites of known master regulators of cardiac development, such as Nkx2-5 and Tbx5.

“A strong cardiac cis-regulatory signature was observed in Category I with the enrichment of binding sites of known master regulators of cardiac development, such as Nkx2-5 and Tbx5, which when mutated account for the genetic causes of CHD (Fig. 2C, i) [2, 25].”

Disruption of signalling pathways such as WNT, BMP, FGF, and retinoic acid pathways that converge towards the kernel can trigger the pathogenesis of CHD.

“Disruption of signalling pathways, such as WNT, BMP, FGF, and retinoic acid pathways, that converge towards a core sub-network (the kernel) can trigger the pathogenesis of CHD [2].”

A cardiac gene regulatory network regulates heart development from a simple tubular structure into a pump under electrophysiological control.

“a cardiac gene regulatory network (GRN) regulates the development of the heart from a simple tubular structure into a pump under electrophysiological control [2].”

The cCREs are possibly controlled by TFs of the cardiac kernel.

“These results point to the possibility that the cCREs are controlled by TFs of the cardiac kernel [2].”

The identified modules recapitulate known modules of the cardiac GRN: the heart development node corresponds to the known kernel of cardiac transcription factors, and other modules correspond to known downstream gene batteries.

“These modules recapitulate known modules of the cardiac GRN: the “heart development” node corresponds to the known kernel of cardiac transcription factors [2]. Other modules such as “muscle gene battery,” “angiogenesis,” “cell cycle and cytoskeleton,” and “mitochondrial genes” modules correspond to known downstream gene batteries of the cardiac GRN [3].”

The function of most CREs is unknown.

“The function of most CREs is unknown; however, there is mounting evidence that sequence mutations in cardiac CREs are associated with congenital heart disease [2, 3].”

Congenital heart disease is associated with alterations in the function of genes constituting the cardiac GRN.

“The functional attribute of the GRN in heart development is illustrated by the association of congenital heart disease (CHD) with alterations in the function of genes constituting the network [2, 4].”

Conventional approaches largely overlook genes that are also expressed in other tissues beside the heart yet may be important for heart development.

“While fruitful, the conventional approaches largely overlook the genes that are also expressed in other tissues beside the heart, yet may be important for heart development [2].”

The kernel comprises several transcription factors such as NKX2-5, TBX5, and GATA4 that act as key regulators integrating cross-regulatory interactions and driving expression of TF-related target genes.

“the kernel comprises several transcription factors (TFs), such as NKX2-5, TBX5, and GATA4 [2], that act as key regulators serving to integrate cross-regulatory interactions and drive the expression of TF-related target genes.”

The majority of these exclusively heart-expressed genes (22/26) have been shown to be involved in heart development and disease and include known cardiac GRN components such as Nkx2-5, Myh6, Myl2, Myl4, and Nppb.

“The majority of these genes (22/26) have been shown to be involved in heart development and disease and includes well-known cardiac GRN components such as Nkx2-5 (Fig. 3A), Myh6, Myl2, Myl4, and Nppb [2].”