title: Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α.
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 neurexin1α (nrxn1α), 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 nrxn1α 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 nrxn1α promoter region in vivo, we identified that Ash1L, a histone methyltransferase, is enriched in the nrxn1α promoter. Neuronal activity triggered binding of Ash1L to the promoter and enriched the histone marker H3K36me2 at the nrxn1α promoter region. Knockout of Ash1L in mice completely abolished the activity-dependent repression of nrxn1α. 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 nrxn1α, thus implicating an important role for epigenetic modification in brain functioning.
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Center for Brain-Inspired Computing Research, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.
authors.forename: Τao
authors.initials: Τ
authors.lastname: Zhu
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Center for Brain-Inspired Computing Research, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Center for Brain-Inspired Computing Research, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Center for Brain-Inspired Computing Research, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Tian
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Center for Brain-Inspired Computing Research, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.
authors.forename: Sanxiong
authors.initials: S
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Center for Brain-Inspired Computing Research, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.
authors.forename: Guanjun
authors.initials: G
authors.lastname: Gao
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Center for Brain-Inspired Computing Research, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.
authors.forename: Ji-Song
authors.initials: JS
authors.lastname: Guan
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D019006:Neural Cell Adhesion Molecules / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; C000600280:Ash1l protein, mouse; D011495:Histone-Lysine N-Methyltransferase