PDF(Pubmed)
Abstract：
Defects in cilia genes, which are critical for cilia formation and function, can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of the networks of cilia genes in ciliopathies remain enigmatic. Herein, we have uncovered the genome-wide redistribution of accessible chromatin regions and extensive alterations of expression of cilia genes during Ellis-van Creveld syndrome (EVC) ciliopathy pathogenesis. Mechanistically, the distinct EVC ciliopathy-activated accessible regions (CAAs) are shown to positively regulate robust changes in flanking cilia genes, which are a key requirement for cilia transcription in response to developmental signals. Moreover, a single transcription factor, ETS1, can be recruited to CAAs, leading to prominent chromatin accessibility reconstruction in EVC ciliopathy patients. In zebrafish, the collapse of CAAs driven by ets1 suppression subsequently causes defective cilia proteins, resulting in body curvature and pericardial oedema. Our results depict a dynamic landscape of chromatin accessibility in EVC ciliopathy patients, and uncover an insightful role for ETS1 in controlling the global transcriptional program of cilia genes by reprogramming the widespread chromatin state.
摘要：
纤毛基因的缺陷,对纤毛的形成和功能至关重要，可引起涉及多个器官和组织的复杂纤毛病综合征;然而,纤毛基因网络在纤毛病变中的潜在调控机制仍然是个谜。在这里，我们发现在Ellis-vanCreveld综合征(EVC)纤毛病发病过程中,易接近染色质区域的全基因组再分布和纤毛基因表达的广泛改变.机械上,不同的EVC纤毛病变激活的可达区域（CAAs）显示正调节侧翼纤毛基因的稳健变化，这是纤毛转录响应发育信号的关键要求。此外，一个单一的转录因子，ETS1，可以招募到CAA，导致EVC纤毛病患者明显的染色质可及性重建。在斑马鱼中,由ets1抑制驱动的CAA崩溃随后导致纤毛蛋白缺陷，导致身体弯曲和心包水肿。我们的结果描绘了EVC纤毛病患者染色质可及性的动态景观，并通过重新编程广泛的染色质状态，揭示ETS1在控制纤毛基因的全球转录程序中的深刻作用。
