Differential Methylation of H3K79 Reveals DOT1L Target Genes and Function in the Cerebellum In Vivo
Differential Methylation of H3K79 Reveals DOT1L Target Genes and Function in the Cerebellum In Vivo
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DOI：
10.1007/s12035-018-1377-1
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发表时间：
2019-06-01
影响因子：
5.1
通讯作者：
Vogel, Tanja
中科院分区：
文献类型：
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作者：
Bovio, Patrick Piero;Franz, Henriette;Vogel, Tanja
端粒沉默1样干扰物（DOT1L）介导组蛋白H3在赖氨酸79 （H3K79）位置的甲基化。小鼠小脑颗粒细胞Dot1l- cko （Atoh1）的条件敲除导致外颗粒层变小，颗粒神经元前体减少。Dot1l-cKO（Atoh1）小鼠的颗粒祖细胞增殖和分化受损，导致小脑变小。突变小鼠在运动行为测试中表现出轻度共济失调。相比之下，浦肯野细胞特异性条件敲除小鼠没有明显的表型。利用微阵列技术对Dot1l-cKO（Atoh1）小脑进行全基因组转录分析，揭示了参与细胞周期、细胞迁移、轴突引导和代谢的基因的变化。为了确定直接的DOT1L靶基因，我们使用了H3K79me2的全基因组分析和转录分析。对DOT1L - cko （Atoh1）中差异甲基化区（DR）和差异表达基因（DE）的分析显示，DOT1L - cko （Atoh1）中总共有12个可能的DOT1L靶基因影响信号传导（Tnfaip8l3, B3galt5）、转录（Otx1）、细胞迁移和轴突引导（Sema4a, Sema5a, Robo1）、胆固醇和脂质代谢（Lss, Cyp51）、细胞周期（Cdkn1a）、钙依赖性细胞粘附或胞外（Pcdh17, Cadps2）和未知功能（Fam174b）。这些靶基因的表达失调可能与Dot1l-cKO（Atoh1）中观察到的共济失调表型有关。
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).