Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Germany; DZHK, German Centre for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Germany.
Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Germany.
Biochim Biophys Acta Gene Regul Mech. 2021 Apr-May;1864(4-5):194702. doi: 10.1016/j.bbagrm.2021.194702. Epub 2021 Mar 8.
The homeodomain transcription factor SHOX2 is involved in the development and function of the heart's primary pacemaker, the sinoatrial node (SAN), and has been associated with cardiac conduction-related diseases such as atrial fibrillation and sinus node dysfunction. To shed light on Shox2-dependent genetic processes involved in these diseases, we established a murine embryonic stem cell (ESC) cardiac differentiation model to investigate Shox2 pathways in SAN-like cardiomyocytes. Differential RNA-seq-based expression profiling of Shox2 and Shox2 ESCs revealed 94 dysregulated transcripts in Shox2 ESC-derived SAN-like cells. Of these, 15 putative Shox2 target genes were selected for further validation based on comparative expression analysis with SAN- and right atria-enriched genes. Network-based analyses, integrating data from the Mouse Organogenesis Cell Atlas and the Ingenuity pathways, as well as validation in mouse and zebrafish models confirmed a regulatory role for the novel identified Shox2 target genes including Cav1, Fkbp10, Igfbp5, Mcf2l and Nr2f2. Our results indicate that genetic networks involving SHOX2 may contribute to conduction traits through the regulation of these genes.
同源盒转录因子 SHOX2 参与心脏主要起搏点窦房结（SAN）的发育和功能，并且与心律失常和窦房结功能障碍等与心脏传导相关的疾病有关。为了阐明与这些疾病相关的 SHOX2 依赖性遗传过程，我们建立了一种鼠胚胎干细胞（ESC）心脏分化模型，以研究 SAN 样心肌细胞中的 SHOX2 途径。基于差异 RNA-seq 的 SHOX2 和 SHOX2 ESC 的表达谱分析揭示了在 SHOX2 ESC 衍生的 SAN 样细胞中 94 个失调的转录本。其中，基于与 SAN 和右心房富集基因的比较表达分析，选择了 15 个推定的 SHOX2 靶基因进行进一步验证。基于 Mouse Organogenesis Cell Atlas 和 Ingenuity pathways 的网络分析，以及在小鼠和斑马鱼模型中的验证证实了 novel identified Shox2 target genes，包括 Cav1、Fkbp10、Igfbp5、Mcf2l 和 Nr2f2，具有调节作用。我们的结果表明，涉及 SHOX2 的遗传网络可能通过这些基因的调节来影响传导特征。
