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
.
Electronic supplementary material
The online version of this article (10.1007/s12035-018-1377-1) contains supplementary material, which is available to authorized users.