背景:转座因子在维持神经发育过程中的基因组结构中起着关键作用。短散布核元素(SINE),转座因子的主要亚型,已知具有CCCTC结合因子(CTCF)的结合位点,并且在协调染色质组织中至关重要。然而,在发育中的大脑中控制SINE活性的调节机制仍然难以捉摸。
结果:在我们的研究中,我们使用ATAC-seq对小鼠神经前体细胞进行了全面的全基因组表观遗传分析,ChIP-seq,全基因组亚硫酸氢盐测序,就地Hi-C,和RNA-seq。我们的发现表明,SET结构域分叉的组蛋白赖氨酸甲基转移酶1(SETDB1)介导的H3K9me3与DNA甲基化结合,限制了神经前体细胞中选择性SINE子集的染色质可及性。机械上,Settb1的丢失会增加CTCF对这些SINE元素的访问,并有助于染色质环的重组。此外,从头环形成有助于差异基因表达,包括有丝分裂途径中富集的基因的失调。这导致在体外和体内对Setdb1进行遗传消融后胚胎脑中细胞增殖的破坏。
结论:总之,我们的研究揭示了小鼠神经前体细胞中SINE的表观遗传调控,提示它们在维持神经发育过程中染色质组织和细胞增殖中的作用。
BACKGROUND: Transposable elements play a critical role in maintaining genome architecture during neurodevelopment. Short Interspersed Nuclear Elements (SINEs), a major subtype of transposable elements, are known to harbor binding sites for the CCCTC-binding factor (CTCF) and pivotal in orchestrating chromatin organization. However, the regulatory mechanisms controlling the activity of SINEs in the developing brain remains elusive.
RESULTS: In our study, we conduct a comprehensive genome-wide epigenetic analysis in mouse neural precursor cells using ATAC-seq, ChIP-seq, whole genome bisulfite sequencing, in situ Hi-C, and RNA-seq. Our findings reveal that the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-mediated H3K9me3, in conjunction with DNA methylation, restricts chromatin accessibility on a selective subset of SINEs in neural precursor cells. Mechanistically, loss of Setdb1 increases CTCF access to these SINE elements and contributes to chromatin loop reorganization. Moreover, de novo loop formation contributes to differential gene expression, including the dysregulation of genes enriched in mitotic pathways. This leads to the disruptions of cell proliferation in the embryonic brain after genetic ablation of Setdb1 both in vitro and in vivo.
CONCLUSIONS: In summary, our study sheds light on the epigenetic regulation of SINEs in mouse neural precursor cells, suggesting their role in maintaining chromatin organization and cell proliferation during neurodevelopment.