Genome-Wide Analysis of MEF2 Transcriptional Program Reveals Synaptic Target Genes and Neuronal Activity-Dependent Polyadenylation Site Selection

Abstract

SUMMARY 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.

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

“…Second, while the role of ALEs and intronic polyA sites in cellular processes is only emerging 11,15 , with different patterns of regulation associated with proliferation depending on cell models 5,6 , our data establish a role of ALE regulation in cell responses to TOP inhibitors. Interestingly, the preferential repression of intragenic polyA sites by DOXO is reminiscent of the recent finding that a UV mimetic reduces the use of internal polyA sites in many yeast genes 24 .…”

“…ALEs are widely regulated in a tissue-specific manner 14 , but little is known about their dynamic regulation. Interestingly, internal ALEs are preferentially upregulated during neuron activation 15 ; a similar regulation was found during cell proliferation in one study 6 , but not in another 5 . Thus, little is known about ALE regulation on a large scale.…”

Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

“…( known regulators of activity-dependent synaptic development programs, such as MEF2A (Lyons et al 1995;Flavell et al 2006;Shalizi et al 2006). MEF2A plays multiple roles in neuronal development, including neuronal survival (Mao et al 1999;Shalizi et al 2003), dendritic differentiation (Shalizi et al 2006), synaptic density of hippocampal neurons (Flavell et al 2006;Barbosa et al 2008), spine density in nucleus accumbens (Pulipparacharuvil et al 2008), and both synapse weakening/elimination and synaptic strengthening (Flavell et al 2008). In our data, expression profiles that correlated with MEF2A include predicted reported MEF2A target genes associated with both synaptic weakening (e.g., ARC, SYNGAP1, and NR4A1) and synaptic strengthening (e.g., BDNF, LGI1).…”

“…Among the four TFs, MEF2A is an upstream regulator of the other three (Flavell et al 2008) and might, therefore, be one of the main regulators of module 1 genes. Supporting this notion, expression profiles of predicted MEF2 target genes and MEF2 target genes identified experimentally in rat hippocampal neurons (Flavell et al 2008) correlated significantly with module 1 expression profiles (Supplemental Fig. S8).…”

“…(A) Schematic representation of MEF2A-associated pathway in cortical neurons. MEF2A can be activated by BDNF, which is also a target of MEF2A (Liu et al 2003;Shalizi et al 2003;Flavell et al 2008), or calciumdependent calcineurin (Flavell et al 2006). Activity-dependent regulation of MEF2A transcription promotes the expression of target genes, such as ARC (activity-regulated cytoskeletal associated protein) and SYNGAP1 (synaptic localized Ras GAP), to promote elimination of excitatory synapses (Flavell et al 2006).…”