title: Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain.
abstract: 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.
authors.affiliation: 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.
authors.forename: Alisa
authors.initials: A
authors.lastname: Mo
authors.affiliation: 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.
authors.forename: Eran A
authors.initials: EA
authors.lastname: Mukamel
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Fred P
authors.initials: FP
authors.lastname: Davis
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Chongyuan
authors.initials: C
authors.lastname: Luo
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Gilbert L
authors.initials: GL
authors.lastname: Henry
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Picard
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Urich
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nery
authors.affiliation: 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.
authors.forename: Terrence J
authors.initials: TJ
authors.lastname: Sejnowski
authors.affiliation: 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.
authors.forename: Ryan
authors.initials: R
authors.lastname: Lister
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Eddy
authors.affiliation: 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.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ecker
authors.affiliation: 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.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nathans
mesh_terms: D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000502:physiology; D057890:Epigenomics / Q000379:methods; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D019579:Neocortex / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000145:classification* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; C489428:Myc protein, mouse; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; C464932:SUN1 protein, mouse; D049452:Green Fluorescent Proteins