Genome-wide identification and characterization of functional neuronal activity-dependent enhancers

Athar N Malik; Thomas Vierbuchen; Martin Hemberg; Alex A Rubin; Emi Ling; Cameron H Couch; Hume Stroud; Ivo Spiegel; Kyle Kai-How Farh; David A Harmin; Michael E Greenberg

doi:10.1038/nn.3808

Genome-wide identification and characterization of functional neuronal activity-dependent enhancers

Nat Neurosci. 2014 Oct;17(10):1330-9. doi: 10.1038/nn.3808. Epub 2014 Sep 7.

Authors

Affiliations

¹ 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.
² Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Ophthalmology, Children's Hospital Boston, Harvard University, Boston, Massachusetts, USA.
⁴ 1] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
⁵ 1] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

PMID: 25195102
PMCID: PMC4297619
DOI: 10.1038/nn.3808

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

2-Amino-5-phosphonovalerate / pharmacology
Animals
CREB-Binding Protein / metabolism
Embryo, Mammalian
Excitatory Amino Acid Antagonists / pharmacology
Gene Expression Regulation / drug effects
Gene Expression Regulation / genetics*
Genome-Wide Association Study
Humans
Jumonji Domain-Containing Histone Demethylases / metabolism
MEF2 Transcription Factors / genetics
MEF2 Transcription Factors / metabolism
Mice
Mice, Inbred C57BL
Mutation / genetics
Neurons / drug effects
Neurons / physiology*
Oncogene Proteins v-fos / metabolism
Potassium Chloride / pharmacology
Sodium Channel Blockers / pharmacology
Tetrodotoxin / pharmacology
Time Factors
Visual Cortex / cytology

Substances

Excitatory Amino Acid Antagonists
MEF2 Transcription Factors
Oncogene Proteins v-fos
Sodium Channel Blockers
Tetrodotoxin
Potassium Chloride
2-Amino-5-phosphonovalerate
Jumonji Domain-Containing Histone Demethylases
Kdm6b protein, mouse
CREB-Binding Protein
Crebbp protein, mouse

Associated data

GEO/GSE21161
GEO/GSE52386
GEO/GSE60049
GEO/GSE60192
GEO/GSM1264352
GEO/GSM1264354
GEO/GSM1264356
GEO/GSM1264358
GEO/GSM1264360
GEO/GSM1264362
GEO/GSM1264364
GEO/GSM1264366
GEO/GSM1264368

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding