Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex.
The mammalian brain contains diverse neuronal types, yet we lack single-cell epigenomic assays that are able to identify and characterize them. DNA methylation is a stable epigenetic mark that distinguishes cell types and marks regulatory elements. We generated >6000 methylomes from single neuronal nuclei and used them to identify 16 mouse and 21 human neuronal subpopulations in the frontal cortex. CG and non-CG methylation exhibited cell type-specific distributions, and we identified regulatory elements with differential methylation across neuron types. Methylation signatures identified a layer 6 excitatory neuron subtype and a unique human parvalbumin-expressing inhibitory neuron subtype. We observed stronger cross-species conservation of regulatory elements in inhibitory neurons than in excitatory neurons. Single-nucleus methylomes expand the atlas of brain cell types and identify regulatory elements that drive conserved brain cell diversity.
Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92037, USA. Swift Biosciences Inc., 58 Parkland Plaza, Suite 100, Ann Arbor, MI 48103, USA. Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA. Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA. Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92037, USA. Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Swift Biosciences Inc., 58 Parkland Plaza, Suite 100, Ann Arbor, MI 48103, USA. Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92037, USA. ecker@salk.edu mbehrens@salk.edu emukamel@ucsd.edu. Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. ecker@salk.edu mbehrens@salk.edu emukamel@ucsd.edu. Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. ecker@salk.edu mbehrens@salk.edu emukamel@ucsd.edu. Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
