Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Role of Tet1 and Tet3 genes and Chromatin Remodeling in Cerebellar Circuit Formation [hMe-Seal]

ABSTRACT: 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 up-regulated and vitamin C activation of Tet enzymes increases the levels of 5-hydroxymethylcytosine (5hmC) at exon start sites of up-regulated genes, notably axon guidance genes and ion channel genes. Knockdown of Tet1 and Tet3 by RNA interference 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. 5hmC-enriched genomic DNA fragments were purified with a selective labeling strategy known as hMe-Seal and carried out DNA deep sequencing using Illumina HiSeq 2500.

ORGANISM(S): Mus musculus

SUBMITTER: Mary E. Hatten

PROVIDER: E-GEOD-74401 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The M-NM-2 subunits of voltage-gated calcium channels regulate surface expression and gating of CaV1 and CaV2 M-NM-11 subunits, and thus contribute to neuronal excitability, neurotransmitter release and calcium-induced gene regulation. In addition certain M-NM-2 subunits are targeted into the nucleus, where they directly interact with the epigenetic machinery. Whereas their involvement in this multitude of functions is reflected by a great molecular heterogeneity of M-NM-2 isoforms derived from four genes and abundant alternative splicing, little is known about the roles of individual M-NM-2 variants in specific neuronal functions. In the present study, an alternatively spliced M-NM-24 subunit lacking the variable N-terminus (M-NM-24e) is identified. It is highly expressed in mouse cerebellum and cultured cerebellar granule cells (CGC) and modulates P/Q-type calcium currents in tsA cells and CaV2.1 surface expression in neurons. Compared to the other two known full-length M-NM-24 variants (M-NM-24a, M-NM-24b) M-NM-24e is most abundantly expressed in the distal axon, but lacks nuclear targeting properties. To examine the importance of nuclear targeting of M-NM-24 subunits for transcriptional regulation, we performed whole genome expression profiling of CGCs from lethargic mice individually reconstituted with M-NM-24a, M-NM-24b, and M-NM-24e. Notably, the number of genes regulated by each M-NM-24 splice variant correlated with the rank order of their nuclear targeting properties (M-NM-24b> M-NM-24a> M-NM-24e). Together these findings support isoform-specific functions of M-NM-24 splice variant in neurons, with M-NM-24b playing a dual role in channel modulation and gene regulation, while the newly detected M-NM-24e variant serves exclusively in calcium channel-dependent functions. We used microarrays to identify gene expression changes caused by M-NM-24 splice variants (M-NM-24a, M-NM-24b and M-NM-24e) of the voltage gated calcium channel in cultured cerebellar granule cells of lethargic mice Cultured cerebellar granule cells from lethargic (129/SvJ background) mice reconstituted with the M-NM-24 splice variants (M-NM-24a, M-NM-24b and M-NM-24e) were compared to eGFP transfected controls

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Role of Tet1 and Tet3 genes and Chromatin Remodeling in Cerebellar Circuit Formation [hMe-Seal]

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