Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.
Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.
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非编码突变的综合分析确定早产中的可用药基因组。
DOI：
10.1126/sciadv.adk1057
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发表时间：
2024-01-19
期刊：
影响因子：
13.6
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Wang C;Wang YJ;Ying L;Wong RJ;Quaintance CC;Hong X;Neff N;Wang X;Biggio JR;Mesiano S;Quake SR;Alvira CM;Cornfield DN;Stevenson DK;Shaw GM;Li J
在美国，早产影响了大约10%的怀孕。尽管存在家族性关联，但识别高危基因座一直是具有挑战性的。我们建立了深度学习和图形模型，通过将怀孕的子宫肌层表观基因组和来自欧洲和非裔美国人队列的大规模患者基因组与自发早产(SPTB)整合在一起，在基本分辨率下对突变效应进行评分。我们发现了以前未知的sPTB基因，这些基因与子宫肌层松弛和炎症反应有关，并且在临产时受孕激素受体调节。我们研究了接受孕激素预防治疗的招募孕妇的这些基因的基因组变异。我们观察到，这些基因的突变负荷可以预测孕激素治疗早产的反应。为了推进治疗开发，我们筛选了大约4000个化合物，确定了影响我们识别的基因的候选分子，并通过实验验证了它们在调节分娩方面的治疗效果。总而言之，我们的综合方法揭示了早产中可用药的基因组，并为研究复杂疾病提供了一个普遍的框架。早产的基因揭示了对黄体酮治疗的反应，并确定了治疗分子。
Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases. Genes in preterm birth reveal responses to progesterone treatment and identify therapeutic molecules.
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通讯作者：
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通讯作者：
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