机构：[1]Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Medicine, West China Second Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.[2]School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.[3]Department of Dermatology, University of Californian San Francisco, San Francisco, CA 94110, USA.[4]Molecular Pathology Unit, Center for Cancer Research, Center for Computational and Integrative Biology, Massachusetts General Hospital, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.[5]Children’s Medical Center Research Institute, Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.[6]Division of Hematology/Oncology, Boston Children’s Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.[7]Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
Genome-wide association studies (GWAS) have identified multiple genomic loci linked to blood cell traits, however understanding the biological relevance of these genetic loci has proven to be challenging. Here, we performed a transcriptome-wide association study (TWAS) integrating gene expression and splice junction usage in neutrophils (N = 196) with a neutrophil count GWAS (N = 173,480 individuals). We identified a total of 174 TWAS-significant genes enriched in target genes of master transcription factors governing neutrophil specification. Knockout of a TWAS candidate at chromosome 5q13.2, TAF9, in CD34+ hematopoietic and progenitor cells (HSPCs) using CRISPR/Cas9 technology showed a significant effect on neutrophil production in vitro. In addition, we identified 89 unique genes significant only for splice junction usage, thus emphasizing the importance of alternative splicing beyond gene expression underlying granulopoiesis. Our results highlight the advantages of TWAS, followed by gene editing, to determine the functions of GWAS loci implicated in hematopoiesis.
基金：
This work was supported by National Key Research
and Development Program of China, Stem Cell and Translational Research
[2017YFA0106800 to L.C., 2017YFA0106500 to L.C.]; National Science Fund for
Excellent Young Scholars [81722004 to L.C.]; Sichuan Science and Technology Program
(No. 2019YFH0137, to Y.Y.) and Chengdu University of Traditional Chinese Medicine
(XSGG2019004, to Y.Y.)
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类|2 区生物学
小类|2 区生物学
最新[2023]版：
大类|1 区生物学
小类|1 区生物学
第一作者：
第一作者机构：[1]Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Medicine, West China Second Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.[2]School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
通讯作者：
推荐引用方式(GB/T 7714)：
Yao Yao,Yang Jia,Qin Qian,et al.Functional annotation of genetic associations by transcriptome-wide association analysis provides insights into neutrophil development regulation.[J].Communications biology.2020,3(1):790.doi:10.1038/s42003-020-01527-7.
APA：
Yao Yao,Yang Jia,Qin Qian,Tang Chao,Li Zhidan...&Rao Shuquan.(2020).Functional annotation of genetic associations by transcriptome-wide association analysis provides insights into neutrophil development regulation..Communications biology,3,(1)
MLA：
Yao Yao,et al."Functional annotation of genetic associations by transcriptome-wide association analysis provides insights into neutrophil development regulation.".Communications biology 3..1(2020):790
生物学