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

doi:10.1016/j.celrep.2023.113392

Integrative multi-omic profiling of adult mouse brain endothelial cells and potential implications in Alzheimer's disease

Cell Rep. 2023 Nov 28;42(11):113392. doi: 10.1016/j.celrep.2023.113392. Epub 2023 Nov 4.

Authors

Min Yu¹, Yage Nie², Jiawen Yang³, Shilun Yang¹, Rui Li⁴, Varsha Rao⁵, Xiaoyan Hu¹, Cheng Fang¹, Simeng Li¹, Dengpan Song⁶, Fuyou Guo⁶, Michael P Snyder⁵, Howard Y Chang⁷, Calvin J Kuo⁸, Jin Xu⁹, Junlei Chang¹⁰

Affiliations

¹ Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
² Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
³ State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China.
⁴ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
⁷ 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.
⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: cjkuo@stanford.edu.
⁹ State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China. Electronic address: xujin7@mail.sysu.edu.cn.
¹⁰ Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. Electronic address: jl.chang@siat.ac.cn.

Abstract

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.

Keywords: Alzheimer's disease; CP: Neuroscience; blood-brain barrier; endothelial cells; multi-omics; proteomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Animals
Blood-Brain Barrier / metabolism
Brain / metabolism
Endothelial Cells* / metabolism
Humans
Mice
Multiomics
Transcription Factors / metabolism

Substances

Transcription Factors

Grants and funding

RM1 HG007735/HG/NHGRI NIH HHS/United States