Description

Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain

Blue B. Lake¹†, Song Chen¹†, Brandon Sos^1,4†, Jean Fan²†, Yun Yung³, Gwendolyn E. Kaeser^3,4, Thu E. Duong^1,5, Derek Gao¹, Jerold Chun³*, Peter Kharchenko²*, Kun Zhang¹*

¹Department of Bioengineering, University of California San Diego, La Jolla, CA, USA; ²Center for Biomedical Informatics, Harvard Medical School, Boston, MA, USA; ³Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; ⁴Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA; ⁵Department of Pediatric Respiratory Medicine, University of California San Diego, La Jolla, CA, USA

†Equally contributed authors

*Corresponding authors

Detailed characterizations of the cell types comprising the immensely complex human brain is essential to understanding its functionalities. Such tasks require highly scalable experimental approaches to examine different aspects of the molecular state of individual cells, as well as their computational integration to produce unified cell state annotations. Here we outline the development of two highly scalable methods (snDrop-Seq and scTHS-Seq), that we have used to acquire nuclear transcriptome and DNA accessibility maps in thousands of single cells from the human adult primary visual cortex. This has enabled fine resolution of human neuronal subtypes, a majority of the non-neuronal cell types, as well as the cell-type specific nuclear transcriptome and DNA accessibility maps. Integrative analysis has allowed us to identify transcription factors and regulatory elements shaping the state of different brain cell types, and to map genetic risk factors of human brain common diseases to specific pathogenic cell types and subtypes.