Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection.
Although many transcription factors are known to control important aspects of neural development, the genome-wide programs that are directly regulated by these factors are not known. We have characterized the genetic program that is activated by MEF2, a key regulator of activity-dependent synapse development. These MEF2 target genes have diverse functions at synapses, revealing a broad role for MEF2 in synapse development. Several of the MEF2 targets are mutated in human neurological disorders including epilepsy and autism spectrum disorders, suggesting that these disorders may be caused by disruption of an activity-dependent gene program that controls synapse development. Our analyses also reveal that neuronal activity promotes alternative polyadenylation site usage at many of the MEF2 target genes, leading to the production of truncated mRNAs that may have different functions than their full-length counterparts. Taken together, these analyses suggest that the ubiquitously expressed transcription factor MEF2 regulates an intricate transcriptional program in neurons that controls synapse development.
Flavell
Steven W
SW
FM Kirby Neurobiology Center, Children's Hospital, and Department of Neurology and Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Kim
Tae-Kyung
TK
Gray
Jesse M
JM
Harmin
David A
DA
Hemberg
Martin
M
Hong
Elizabeth J
EJ
Markenscoff-Papadimitriou
Eirene
E
Bear
Daniel M
DM
Greenberg
Michael E
ME
D000704:Analysis of Variance; D000818:Animals; D001931:Brain Mapping; D002467:Cell Nucleus / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004622:Embryo, Mammalian; D005106:Exploratory Behavior; D023281:Genomics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D064326:MEF2 Transcription Factors; D008297:Male; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D009422:Nervous System Diseases / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010775:Photic Stimulation / Q000379:methods; D026723:Polyadenylation / Q000235:genetics*; D051381:Rats; D020318:Rats, Long-Evans; D013569:Synapses / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology*; D014793:Visual Cortex / Q000502:physiology
D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors; D012321:DNA-Directed RNA Polymerases