Neuron
Volume 89, Issue 1, 6 January 2016, Pages 100-112
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Article
Role of Tet1/3 Genes and Chromatin Remodeling Genes in Cerebellar Circuit Formation

https://doi.org/10.1016/j.neuron.2015.11.030Get rights and content
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Highlights

  • Pivotal changes occur in chromatin-modifying genes during circuit formation

  • TET activation elevates 5hmC and axon guidance and ion channel gene levels

  • 5hmC maps to exon start sites of genes with the highest expression levels

  • Tet1/3 RNAi knockdown inhibits dendritic arborization in postmigratory neurons

Summary

Although mechanisms underlying early steps in cerebellar development are known, evidence is lacking on genetic and epigenetic changes during the establishment of the synaptic circuitry. Using metagene analysis, we report pivotal changes in multiple reactomes of epigenetic pathway genes in cerebellar granule cells (GCs) during circuit formation. During this stage, Tet genes are upregulated and vitamin C activation of Tet enzymes increases the levels of 5-hydroxymethylcytosine (5hmC) at exon start sites of upregulated genes, notably axon guidance genes and ion channel genes. Knockdown of Tet1 and Tet3 by RNAi in ex vivo cerebellar slice cultures inhibits dendritic arborization of developing GCs, a critical step in circuit formation. These findings demonstrate a role for Tet genes and chromatin remodeling genes in the formation of cerebellar circuitry.

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