Department of Pathology and Women's Hospital, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.
Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou, China.
Angiogenesis. 2023 May;26(2):217-232. doi: 10.1007/s10456-023-09869-6. Epub 2023 Feb 6.
Precise and specific spatiotemporal domains of gene expression regulation are critical for embryonic development. Recent studies have identified GLTSCR1 as a gene transcriptional elongation regulator in cancer research. However, the function of GLTSCR1, especially in embryonic development, remains poorly understood. Here, we found that GLTSCR1 was essential for cardiac development because Gltscr1 knockout (Gltscr1) led to embryonic lethality in mice with severe congenital heart defects (CHDs). Ventricular septal defect and double outflow right ventricular were also observed in neural crest cells with conditional deletion of Gltscr1, which were associated with neonatal lethality in mice. Mechanistically, GLTSCR1 deletion promoted NPPA expression by coordinating the CHD risk G allele of rs56153133 in the NPPA enhancer and releasing the transcription factor ZNF740-binding site on the NPPA promoter. These findings demonstrated that GLTSCR1 acts as a candidate CHD-related gene.
基因表达调控的精确和特定时空域对于胚胎发育至关重要。最近的研究已经确定 GLTSCR1 是癌症研究中的一种基因转录延伸调节剂。然而，GLTSCR1 的功能，特别是在胚胎发育中的功能，仍知之甚少。在这里，我们发现 GLTSCR1 对于心脏发育是必不可少的，因为 Gltscr1 敲除（Gltscr1）导致小鼠出现严重的先天性心脏缺陷（CHDs）而导致胚胎致死。在条件性删除 Gltscr1 的神经嵴细胞中也观察到室间隔缺损和双流出道右心室，这与小鼠的新生儿致死有关。在机制上，GLTSCR1 的缺失通过协调 NPPA 增强子中 CHD 风险 G 等位基因 rs56153133 并释放 NPPA 启动子上的转录因子 ZNF740 结合位点来促进 NPPA 的表达。这些发现表明 GLTSCR1 是候选 CHD 相关基因。
