PO.MCB08.04 · 分子与细胞生物学

肺细胞单细胞全长转录组揭示超越eQTL的遗传效应对异构体调控的影响

Single-cell full-length transcriptome of lung cells reveals genetic effects on isoform regulation beyond eQTL

编号 5924 展板 12 时间 4/21 02:00–05:00 区域 Section 21 主讲 Bolun Li, PhD

分会场 Genetic and Transcriptomic Dissection of Cancer Evolution

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作者与单位 Authors & Affiliations

Bolun Li¹, Thong Luong², Elelta Sisay³, Jinhu Yin⁴, Zixuan Zhang⁵, Ju Hye Shin⁶, Jinyoung Byun⁷, Yoon Soo Chang⁶, Maria Teresa Landi⁸, Nat Rothman⁹, Erping Long¹⁰, Qing Lan¹¹, Christopher I. Amos⁷, Tongwu Zhang¹², Jianxin Shi¹³, Nicholas Mancuso¹⁴, Haoyu Zhang¹⁵, Jin Gu Lee¹⁶, Eon Young Kim⁶, Jiyeon Choi¹⁷

¹NIH-NCI, Bethesda, MD,²National Cancer Institute, Rockville, MD,³NCI, Rockville, MD,⁴DCEG, National Cancer Institute, Rockville, MD,⁵Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,⁶Yonsei University College of Medicine, Seoul, Korea, Republic of,⁷University of New Mexico Comprehensive Cancer Center, Albuquerque, NM,⁸Senior Investigator, Dceg, NCI-DCEG (Division of Cancer Epidemiology and Genetics), Bethesda, MD,⁹NCI-DCEG, BETHESDA, MD,¹⁰Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,¹¹NCI Div. of Cancer Epidemiology & Genetics, Bethesda, MD,¹²DCEG, National Cancer Insititute, Rockville, MD,¹³National Cancer Insititute, Potomac, MD,¹⁴Keck School of Medicine, University of Southern California, Los Angeles, CA,¹⁵National Cancer Inst. Div. of Cancer Epidemiology & Genetics, Bethesda, MD,¹⁶Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea, Republic of,¹⁷NCI, Bethesda, MD

摘要 Abstract

中文摘要

背景:肺癌是全球最常见且危及生命的癌症之一。遗传因素在吸烟者和非吸烟者的肺癌风险中均有贡献,全基因组关联研究(GWAS)已从不同人群中鉴定出>50个基因组位点。表达数量性状位点(eQTL)和剪接QTL(sQTL)分析可揭示遗传效应对基因水平或转录本异构体水平调控的不同作用,这些作用促成GWAS信号,有助于鉴定靶基因并阐明病因。然而,当前使用块状组织短读长测序的sQTL研究无法捕获全长和新异构体,或促成肿瘤发生的细胞类型特异性剪接事件。方法:我们利用单细胞长读长RNA测序,基于129名从不吸烟的韩国女性建立了异构体水平的肺细胞图谱。通过FACS分选富集了肺癌起源的上皮细胞。通过差异分析鉴定各肺细胞类型的异构体特征。我们使用jaxQTL负二项模型对伪块状计数进行异构体水平QTL(isoQTL)定位。通过与GWAS进行共定位和全转录组关联研究(TWAS)来优先筛选易感异构体。结果:我们从360,133个肺细胞中鉴定出325,865个全长异构体,其中83%为GENCODE v32中未注释的新异构体。我们鉴定出37种肺细胞类型的异构体水平特征,其中67.2%的差异异构体显示出比基因水平更大的差异。异构体QTL(isoQTL)鉴定出在基于块状组织的sQTL研究中未报道的基因,这归因于细胞类型特异性和未注释的异构体。与条形码匹配的短读长表达数据相比,46%的isoQTL在同一细胞类型中未与eQTL共定位。一致地,isoQTL明显富集于剪接和转录后调控的功能元件中。isoQTL与肺癌及性状GWAS信号的共定位提名了候选异构体,其中69%在基因水平此前未被报道。此外,71%的GWAS共定位异构体独立于eQTL,包括与肺癌相关的PPIL6-207。祖先匹配的肺腺癌TWAS从亚阈值GWAS区域鉴定出12个异构体,其中包括谱系或细胞类型特异性基因。结论:我们利用单细胞长读长测序建立了异构体水平的肺细胞图谱,并检测出细胞类型特异性且独立于eQTL的isoQTL。这一异构体水平资源推进了我们对细胞类型特异性异构体调控及其对肺癌和疾病贡献的理解。

查看英文原文 English abstract

Background : Lung cancer is one of the most prevalent and life-threatening cancers worldwide. Genetic factors contribute to lung cancer risk in smokers and non-smokers, and genome-wide association studies (GWAS) identified > 50 genomic loci from diverse populations. Expression quantitative trait loci (eQTL) and splicing QTL (sQTL) analyses can reveal distinct genetic effects on gene- or transcript isoform-level regulation contributing to GWAS signals to identify target genes and elucidate etiology. However, current sQTL studies using short-read sequencing of bulk tissues fail to capture full-length and novel isoforms or cell-type-specific splicing events contributing to tumorigenesis. Methods : We present an isoform-level lung cell atlas from 129 never-smoking Korean women using single-cell long-read RNA-sequencing. Epithelial cells, where lung cancer originate, were enriched by FACS sorting. Isoform signatures of each lung cell type were identified by differential analysis. We mapped isoform-level QTLs (isoQTLs) using jaxQTL negative binomial model of pseudo-bulk counts. Colocalization and transcriptome-wide association study (TWAS) with GWAS were performed to prioritize susceptibility isoforms. Results: We identified 325,865 full-length isoforms from 360,133 lung cells, where 83% are novel isoforms not annotated in GENCODE v32. We identified isoform-level signatures of 37 lung cell types, where 67.2% of differential isoforms display larger differences than in gene levels. Isoform-QTLs (isoQTLs) identified unreported genes in bulk tissue-based sQTL studies attributed to cell-type-specific and unannotated isoforms. Compared to the barcode-matched short-read expression data, 46% of isoQTLs did not colocalize with eQTLs in the same cell type. Consistently, isoQTLs were distinctly enriched in the functional elements of splicing and post-transcriptional regulation. Colocalization of isoQTLs with lung cancer and trait GWAS signals nominated candidate isoforms, where 69% were previously unreported at the gene level. Moreover, 71% of GWAS-colocalized isoforms were independent from eQTLs, including PPIL6-207 for lung cancer. TWAS of ancestry-matched lung adenocarcinoma identified 12 isoforms from the sub-threshold GWAS regions, which include lineage or cell-type-specific genes. Conclusions: We established an isoform-level lung cell atlas using single-cell long-read sequencing and detected isoQTLs that are cell-type-specific and independent from eQTLs. This isoform-level resource advances our understanding of cell-type-specific isoform regulation and its contribution to lung cancer and diseases.

利益披露 Disclosure

B. Li, None.. E. Sisay, None.. J. Yin, None.. Z. Zhang, None.. J. Shin, None.. J. Byun, None.. E. Long, None.. C. I. Amos, None.. T. Zhang, None.. N. Mancuso, None.. J. Lee, None.. E. Kim, None.

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