title: Genome-wide identification and characterization of functional neuronal activity-dependent enhancers.
abstract: Experience-dependent gene transcription is required for nervous system development and function. However, the DNA regulatory elements that control this program of gene expression are not well defined. Here we characterize the enhancers that function across the genome to mediate activity-dependent transcription in mouse cortical neurons. We find that the subset of enhancers enriched for monomethylation of histone H3 Lys4 (H3K4me1) and binding of the transcriptional coactivator CREBBP (also called CBP) that shows increased acetylation of histone H3 Lys27 (H3K27ac) after membrane depolarization of cortical neurons functions to regulate activity-dependent transcription. A subset of these enhancers appears to require binding of FOS, which was previously thought to bind primarily to promoters. These findings suggest that FOS functions at enhancers to control activity-dependent gene programs that are critical for nervous system function and provide a resource of functional cis-regulatory elements that may give insight into the genetic variants that contribute to brain development and disease.
authors.affiliation: 1] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] MD-PhD Program, Harvard Medical School, Boston, Massachusetts, USA. [3] Division of Health Sciences and Technology, Harvard Medical School and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Athar N
authors.initials: AN
authors.lastname: Malik
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vierbuchen
authors.affiliation: Department of Ophthalmology, Children's Hospital Boston, Harvard University, Boston, Massachusetts, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Hemberg
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Rubin
authors.affiliation: 1] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Emi
authors.initials: E
authors.lastname: Ling
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Cameron H
authors.initials: CH
authors.lastname: Couch
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hume
authors.initials: H
authors.lastname: Stroud
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ivo
authors.initials: I
authors.lastname: Spiegel
authors.affiliation: 1] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Kyle Kai-How
authors.initials: KK
authors.lastname: Farh
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Harmin
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014793:Visual Cortex / Q000166:cytology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D064326:MEF2 Transcription Factors; D016761:Oncogene Proteins v-fos; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D011189:Potassium Chloride; D015763:2-Amino-5-phosphonovalerate; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse