Single nucleus multi-omics identifies human cortical cell regulatory genome diversity

Chongyuan Luo, Hanqing Liu, Fangming Xie, Ethan J. Armand, Kimberly Siletti, Trygve E. Bakken, Rongxin Fang, Wayne I. Doyle, Tim Stuart, Rebecca D. Hodge, Lijuan Hu, Bang An Wang, Zhuzhu Zhang, Sebastian Preissl, Dong Sung Lee, Jingtian Zhou, Sheng Yong Niu, Rosa Castanon, Anna Bartlett, Angeline RivkinXinxin Wang, Jacinta Lucero, Joseph R. Nery, David A. Davis, Deborah C. Mash, Rahul Satija, Jesse R. Dixon, Sten Linnarsson, Ed Lein, M. Margarita Behrens, Bing Ren, Eran A. Mukamel, Joseph R. Ecker

Research output: Contribution to journalArticlepeer-review


Single-cell technologies measure unique cellular signatures but are typically limited to a single modality. Computational approaches allow the fusion of diverse single-cell data types, but their efficacy is difficult to validate in the absence of authentic multi-omic measurements. To comprehensively assess the molecular phenotypes of single cells, we devised single-nucleus methylcytosine, chromatin accessibility, and transcriptome sequencing (snmCAT-seq) and applied it to postmortem human frontal cortex tissue. We developed a cross-validation approach using multi-modal information to validate fine-grained cell types and assessed the effectiveness of computational data fusion methods. Correlation analysis in individual cells revealed distinct relations between methylation and gene expression. Our integrative approach enabled joint analyses of the methylome, transcriptome, chromatin accessibility, and conformation for 63 human cortical cell types. We reconstructed regulatory lineages for cortical cell populations and found specific enrichment of genetic risk for neuropsychiatric traits, enabling the prediction of cell types that are associated with diseases.

Original languageEnglish (US)
Article number100107
JournalCell Genomics
Issue number3
StatePublished - Mar 9 2022


  • brain
  • epigenomics
  • methylation
  • multi-omics
  • single cell

ASJC Scopus subject areas

  • Genetics
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)


Dive into the research topics of 'Single nucleus multi-omics identifies human cortical cell regulatory genome diversity'. Together they form a unique fingerprint.

Cite this