Differential Methylation of H3K79 Reveals DOT1L Target Genes and Function in the Cerebellum In Vivo.
Mol Neurobiol, 2019/6;56(6):4273-4287.
Bovio PP[1, 2], Franz H[1], Heidrich S[1], Rauleac T[1], Kilpert F[3], Manke T[3], Vogel T[4]
Affiliations
PMID: 30302725DOI: 10.1007/s12035-018-1377-1
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Abstract
The disruptor of telomeric silencing 1-like (DOT1L) mediates methylation of histone H3 at position lysine 79 (H3K79). Conditional knockout of Dot1l in mouse cerebellar granule cells (Dot1l-cKOAtoh1) led to a smaller external granular layer with fewer precursors of granule neurons. Dot1l-cKOAtoh1 mice had impaired proliferation and differentiation of granular progenitors, which resulted in a smaller cerebellum. Mutant mice showed mild ataxia in motor behavior tests. In contrast, Purkinje cell-specific conditional knockout mice showed no obvious phenotype. Genome-wide transcription analysis of Dot1l-cKOAtoh1 cerebella using microarrays revealed changes in genes that function in cell cycle, cell migration, axon guidance, and metabolism. To identify direct DOT1L target genes, we used genome-wide profiling of H3K79me2 and transcriptional analysis. Analysis of differentially methylated regions (DR) and differentially expressed genes (DE) revealed in total 12 putative DOT1L target genes in Dot1l-cKOAtoh1 affecting signaling (Tnfaip8l3, B3galt5), transcription (Otx1), cell migration and axon guidance (Sema4a, Sema5a, Robo1), cholesterol and lipid metabolism (Lss, Cyp51), cell cycle (Cdkn1a), calcium-dependent cell-adhesion or exocytosis (Pcdh17, Cadps2), and unknown function (Fam174b). Dysregulated expression of these target genes might be implicated in the ataxia phenotype observed in Dot1l-cKOAtoh1.
Keywords: Ataxia; Atoh1; Epigenetics; Purkinje cell
MeSH terms
Animals; Axon Guidance; Cell Cycle; Cell Differentiation; Cell Movement; Cell Proliferation; Cell Survival; Cerebellum; Cholesterol; Gene Expression Regulation; Histone-Lysine N-Methyltransferase; Histones; Lysine; Methylation; Methyltransferases; Mice, Inbred C57BL; Mice, Knockout; Neural Stem Cells; Neurons; Stress, Physiological; Transcriptome
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