Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1?.

ABSTRACT: Activity-dependent transcription is critical for the regulation of long-term synaptic plasticity and plastic rewiring in the brain. Here, we report that the transcription of neurexin1? (nrxn1?), a presynaptic adhesion molecule for synaptic formation, is regulated by transient neuronal activation. We showed that 10?minutes of firing at 50?Hz in neurons repressed the expression of nrxn1? for 24?hours in a primary cortical neuron culture through a transcriptional repression mechanism. By performing a screening assay using a synthetic zinc finger protein (ZFP) to pull down the proteins enriched near the nrxn1? promoter region in vivo, we identified that Ash1L, a histone methyltransferase, is enriched in the nrxn1? promoter. Neuronal activity triggered binding of Ash1L to the promoter and enriched the histone marker H3K36me2 at the nrxn1? promoter region. Knockout of Ash1L in mice completely abolished the activity-dependent repression of nrxn1?. Taken together, our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1?, thus implicating an important role for epigenetic modification in brain functioning.

SUBMITTER: Zhu ? 

PROVIDER: S-EPMC4882582 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature