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克里斯普尔查揭示了在胰腺分化中对ONECUT1的长距离增强剂,并将糖尿病风险变体与糖尿病风险变体联系起来

Samuel Joseph Kaplan¹, Wilfred Wong², Jielin Yan³

¹Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College, New York, NY 10065, USA; Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

|August 20, 2024

概括

研究人员发现了一种新的增强剂,ONECUT1e-664kb,对胰腺发育至关重要,与糖尿病有关. 删除这种增强剂会损害胰腺分化和干细胞中的ONECUT1表达.

科学领域:

遗传学是一个遗传学.
发展生物学发展生物学
内分泌学在内分泌学.

背景情况:

功能增强剂注释是理解基因调节和疾病的关键. 在与疾病相关的环境中识别增强剂,如糖尿病,是具有挑战性的.
由于编码突变,ONECUT1基因与胰腺发育和糖尿病有关.

研究的目的:

通过不偏见的方法发现参与胰腺发育的新增剂.
研究一种特定增强剂ONECUT1e-664kb在胰腺分化中的作用及其与糖尿病的联系.

主要方法:

在胰腺分化过程中,在人类多能干细胞 (hPSCs) 中进行CRISPR干扰 (CRISPRi) 选.
在hPSCs中通过同胞性缺失对ONECUT1e-664kb增强剂的功能验证.
在增强剂内对2型糖尿病相关变体 (rs528350911) 的分析及其对转录因子结合的影响.

主要成果:

确定了ONECUT1e-664kb作为一个关键增强器,距离ONECUT1促进器有664kb.
在hPSCs中ONECUT1e-664kb的同卵性除导致ONECUT1表达的几乎完全丧失和胰腺分化受损.
在ONECUT1e-664kb中,一种2型糖尿病变体破坏了GATA动机,减少了胰腺转录因子 (GATA4,GATA6,FOXA2) 的结合.

结论:

在疾病相关系统中发现无偏的增强剂是有效的,用于识别监管元素.
ONECUT1e-664kb在胰腺发育中起着至关重要的作用,并且与糖尿病病原发生有机械联系.
这项研究通过剖析增强器功能,提供了对单一性和复杂性糖尿病形式的洞察.

关键词:

CP: 发育生物学科普:分子生物学分子生物学在CRISPRi的屏幕上.在 ONECUT1 上.这就是T2D.这就是VUS VUS VUS.增强剂是一种增强剂.新生儿糖尿病新生儿糖尿病没有编码的变种.胰腺发育胰腺发育 2 型糖尿病 2 型糖尿病不确定意义的变种.

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