Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain.
Neuronal diversity is essential for mammalian brain function but poses a challenge to molecular profiling. To address the need for tools that facilitate cell-type-specific epigenomic studies, we developed the first affinity purification approach to isolate nuclei from genetically defined cell types in a mammal. We combine this technique with next-generation sequencing to show that three subtypes of neocortical neurons have highly distinctive epigenomic landscapes. Over 200,000 regions differ in chromatin accessibility and DNA methylation signatures characteristic of gene regulatory regions. By footprinting and motif analyses, these regions are predicted to bind distinct cohorts of neuron subtype-specific transcription factors. Neuronal epigenomes reflect both past and present gene expression, with DNA hyper-methylation at developmentally critical genes appearing as a novel epigenomic signature in mature neurons. Taken together, our findings link the functional and transcriptional complexity of neurons to their underlying epigenomic diversity.
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Cognitive Science, University of California San Diego, La Jolla, CA 92037, USA. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; The ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, Crawley, Western Australia 6009, Australia. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: ecker@salk.edu. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jnathans@jhmi.edu.
