Integrative multi-omic profiling of adult mouse brain endothelial cells and potential implications in Alzheimer’s disease
Min Yu,
Yage Nie,
Jiawen Yang,
Shilun Yang,
Rui Li,
Varsha Rao,
Xiaoyan Hu,
Cheng Fang,
Simeng Li,
Dengpan Song,
Fuyou Guo,
Michael P. Snyder,
Howard Y. Chang,
Calvin J. Kuo,
Jin Xu,
Junlei Chang
Affiliations
Min Yu
Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
Yage Nie
Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
Jiawen Yang
State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
Shilun Yang
Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
Rui Li
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
Varsha Rao
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
Xiaoyan Hu
Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
Cheng Fang
Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
Simeng Li
Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
Dengpan Song
Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
Fuyou Guo
Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
Michael P. Snyder
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
Howard Y. Chang
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
Calvin J. Kuo
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Corresponding author
Jin Xu
State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China; Corresponding author
Junlei Chang
Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Corresponding author
Summary: The blood-brain barrier (BBB) is primarily manifested by a variety of physiological properties of brain endothelial cells (ECs), but the molecular foundation for these properties remains incompletely clear. Here, we generate a comprehensive molecular atlas of adult brain ECs using acutely purified mouse ECs and integrated multi-omics. Using RNA sequencing (RNA-seq) and proteomics, we identify the transcripts and proteins selectively enriched in brain ECs and demonstrate that they are partially correlated. Using single-cell RNA-seq, we dissect the molecular basis of functional heterogeneity of brain ECs. Using integrative epigenomics and transcriptomics, we determine that TCF/LEF, SOX, and ETS families are top-ranked transcription factors regulating the BBB. We then validate the identified brain-EC-enriched proteins and transcription factors in normal mouse and human brain tissue and assess their expression changes in mice with Alzheimer’s disease. Overall, we present a valuable resource with broad implications for regulation of the BBB and treatment of neurological disorders.
