Network-driven discovery yields new insight into Shox2-dependent cardiac rhythm control

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Genetics

Background:

• The homeodomain transcription factor SHOX2 plays a role in sinoatrial node (SAN) development and function.
• SHOX2 is implicated in cardiac conduction disorders, including atrial fibrillation and sinus node dysfunction.

Purpose of the Study:

• To investigate Shox2-dependent genetic pathways in SAN-like cardiomyocytes using a murine embryonic stem cell (ESC) cardiac differentiation model.
• To identify novel Shox2 target genes involved in cardiac conduction.

Main Methods:

• Murine ESC cardiac differentiation model.
• Differential RNA-sequencing (RNA-seq) for expression profiling of Shox2 wild-type and knockout cells.
• Comparative expression analysis, network-based analyses, and validation in mouse and zebrafish models.

Main Results:

• 94 dysregulated transcripts were identified in Shox2 knockout ESC-derived SAN-like cells.
• 15 putative Shox2 target genes were selected and validated.
• Confirmed regulatory roles for novel Shox2 targets including Cav1, Fkbp10, Igfbp5, Mcf2l, and Nr2f2.

Conclusions:

• Genetic networks involving SHOX2 contribute to cardiac conduction traits.
• SHOX2 regulates novel target genes that influence cardiac electrophysiology.