Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex

Science 2017

Luo, Chongyuan and Keown, Christopher L. and Kurihara, Laurie and Zhou, Jingtian and He, Yupeng and Li, Junhao and Castanon, Rosa and Lucero, Jacinta and Nery, Joseph R. and Sandoval, Justin P. and Bui, Brian and Sejnowski, Terrence J. and Harkins, Timothy T. and Mukamel, Eran A. and Behrens, M. Margarita and Ecker, Joseph R.

Abstract

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.

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