| First Author | Bovio PP | Year | 2019 |
| Journal | Mol Neurobiol | Volume | 56 |
| Issue | 6 | Pages | 4273-4287 |
| PubMed ID | 30302725 | Mgi Jnum | J:277666 |
| Mgi Id | MGI:6342331 | Doi | 10.1007/s12035-018-1377-1 |
| Citation | Bovio PP, et al. (2019) Differential Methylation of H3K79 Reveals DOT1L Target Genes and Function in the Cerebellum In Vivo. Mol Neurobiol 56(6):4273-4287 |
| abstractText | 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-cKO(Atoh1)) led to a smaller external granular layer with fewer precursors of granule neurons. Dot1l-cKO(Atoh1) 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-cKO(Atoh1) 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-cKO(Atoh1) 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-cKO(Atoh1). |
