A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network.

Background: The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF. The pathophysiological basis of AF in the context of HF is presumed to result from atrial remodeling. Upregulation of the transcription factor FOG2 (friend of GATA2; encoded by ) is observed in human ventricles during HF and causes HF in mice.

Common pathways regulate Type III TGFβ receptor-dependent cell invasion in epicardial and endocardial cells.

Epithelial-Mesenchymal Transformation (EMT) and the subsequent invasion of epicardial and endocardial cells during cardiac development is critical to the development of the coronary vessels and heart valves. The transformed cells give rise to cardiac fibroblasts and vascular smooth muscle cells or valvular interstitial cells, respectively. The Type III Transforming Growth Factor β (TGFβR3) receptor regulates EMT and cell invasion in both cell types, but the signaling mechanisms downstream of TGFβR3 are not well understood.

Epicardial-myocardial signaling directing coronary vasculogenesis.

The establishment of the coronary circulation is critical for the development of the embryonic heart. Over the last several years, there has been tremendous progress in elucidating the pathways that control coronary development. Interestingly, many of the pathways that regulate the development of the coronary vasculature are distinct from those governing vasculogenesis in the rest of the embryo.

FOG-1-mediated recruitment of NuRD is required for cell lineage re-enforcement during haematopoiesis.

The transcriptional co-factor Friend of GATA1 (FOG-1) has been shown to interact with subunits of the nucleosome remodelling and histone deacetylase (NuRD) complex through a specific motif located at its N-terminus. To test the importance of FOG-1/NuRD interaction for haematopoiesis in vivo, we generated mice with a mutation that specifically disrupts FOG-1/NuRD interaction (FOG-1(R3K5A)). Homozygous FOG-1(R3K5A) mice were found to have splenomegaly, extramedullary erythropoiesis, granulocytosis and thrombocytopaenia secondary to a block in megakaryocyte maturation.

Fog1 is required for cardiac looping in zebrafish.

To further our understanding of FOG gene function during cardiac development, we utilized zebrafish to examine FOG's role in the early steps of heart morphogenesis. We identified fragments of three fog genes in the zebrafish genomic database and isolated full-length coding sequences for each of these genes by using a combination of RT-PCR and 5'-RACE. One gene was similar to murine FOG-1 (fog1), while the remaining two were similar to murine FOG-2 (fog2a and fog2b).

Transforming growth factor-beta stimulates epithelial-mesenchymal transformation in the proepicardium.

The proepicardium (PE) migrates over the heart and forms the epicardium. A subset of these PE-derived cells undergoes epithelial-mesenchymal transformation (EMT) and gives rise to cardiac fibroblasts and components of the coronary vasculature. We report that transforming growth factor-beta (TGFbeta) 1 and TGFbeta2 increase EMT in PE explants as measured by invasion into a collagen gel, loss of cytokeratin expression, and redistribution of ZO1.

Coronary vessel development: the epicardium delivers.

Coronary artery disease accounts for 54% of all cardiovascular disease in the United States. Understanding how coronary vessels develop is likely to uncover novel drug targets and therapeutic strategies that will be useful in directing the repair or remodeling of coronary vessels in adults. Recent insights have identified the importance of cells derived from the proepicardium and epicardium in the formation of coronary vessels.

Expression of the type III TGFbeta receptor during chick organogenesis.

Transforming growth factor beta (TGFbeta) is a regulator of embryonic development. The role of specific TGFbeta receptors is emerging, and a unique role for the type III TGFbeta receptor (TBRIII) has been suggested. We report the pattern of TBRIII expression in chicken embryos from 2 to 14 days in ovo.