Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes.
Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes.
复制标题
DOI：
10.7554/elife.62522
复制
发表时间：
2020-11-09
期刊：
影响因子：
7.7
通讯作者：
NHLBI LungMap Consortium
中科院分区：
文献类型：
--
作者：
Wang A;Chiou J;Poirion OB;Buchanan J;Valdez MJ;Verheyden JM;Hou X;Kudtarkar P;Narendra S;Newsome JM;Guo M;Faddah DA;Zhang K;Young RE;Barr J;Sajti E;Misra R;Huyck H;Rogers L;Poole C;Whitsett JA;Pryhuber G;Xu Y;Gaulton KJ;Preissl S;Sun X;NHLBI LungMap Consortium
与COVID-19相关的呼吸衰竭已成为人们关注的焦点。在这里，我们从妊娠~30周、~3年和~30岁的供体中获得了90,980个细胞核的单核可及染色质谱和46,500个细胞核的匹配单核转录组。我们绘制了候选顺式调控元件（cCREs），并将它们与假定的靶基因联系起来。我们在肺泡2型细胞中发现了与SARS-CoV-2宿主进入基因TMPRSS2相关的远端cCREs，其活性随着年龄的增加而增加，这些细胞具有免疫调节特征，并携带与呼吸特征相关的变异。在3p21.31 COVID-19风险位点，一个候选变异与SLC6A20相关的远端cCRE重叠，SLC6A20是一种在肺泡细胞中表达的基因，已知与SARS-CoV-2受体ACE2具有功能关联。我们的研究结果为不同年龄的个体肺细胞类型中与COVID-19相关的基因的调控逻辑提供了见解。更广泛地说，这些数据集将有助于解释肺部疾病的风险位点。
Respiratory failure associated with COVID-19 has placed focus on the lungs. Here, we present single-nucleus accessible chromatin profiles of 90,980 nuclei and matched single-nucleus transcriptomes of 46,500 nuclei in non-diseased lungs from donors of ~30 weeks gestation,~3 years and ~30 years. We mapped candidate cis-regulatory elements (cCREs) and linked them to putative target genes. We identified distal cCREs with age-increased activity linked to SARS-CoV-2 host entry gene TMPRSS2 in alveolar type 2 cells, which had immune regulatory signatures and harbored variants associated with respiratory traits. At the 3p21.31 COVID-19 risk locus, a candidate variant overlapped a distal cCRE linked to SLC6A20, a gene expressed in alveolar cells and with known functional association with the SARS-CoV-2 receptor ACE2. Our findings provide insight into regulatory logic underlying genes implicated in COVID-19 in individual lung cell types across age. More broadly, these datasets will facilitate interpretation of risk loci for lung diseases.