The role of the DNA Methyltransferase1 (DNMT1) in the development of somatostatin (SST)-positive cortical interneurons

GABA能中间神经元的巨大异质性集合的空间和时间抑制作用极大地影响皮层信息处理，这反映在涉及缺陷皮层抑制的疾病如自闭症、癫痫和精神分裂症中。解密的监管网络，直接亚型特异性皮层中间神经元的发展是非常感兴趣的，因为这有助于确定关键事件牵连在这些疾病的病因。基因调控的表观遗传机制，如DNA甲基化（DNMTs）和组蛋白修饰执行的DNA甲基化在塑造发育过程和人类健康引起越来越多的关注。几项研究将精神分裂症患者胚胎和成人皮质中间神经元亚群中DNA甲基转移酶1（DNMT 1）的表达水平和功能改变联系起来。尽管越来越多的证据支持表观遗传标记指导细胞类型特异性发育的相关性，但关于它们在离散发育过程和皮质中间神经元亚型特异性成熟中的功能意义知之甚少。通过单细胞转录组学，整体转录组学和FAC-sorted胚胎中间神经元的甲基化组分析结合功能验证实验，我们最近发现DNMT 1主要通过与组蛋白修饰的相互作用促进起源于视前区（POA）的中间神经元的迁移。相反，初步实验表明DNMT 1的DNA甲基化作用似乎对SST阳性中间神经元的正常发育至关重要，可能参与建立指导亚型特异性发育的转录程序。SST-中间神经元主要在MGE中产生，并且已经显示在精神分裂症和其他人类精神和神经障碍中受到影响。因此，我们在这里的目的是剖析DNMT 1在SST阳性中间神经元有丝分裂后成熟的作用。为此，我们将采用创新和多样化的方法，包括小鼠遗传学，高通量测序和功能性生物测定。为了确定在SST-中间神经元成熟过程中DNMT 1调节的过程，将对胚胎、出生后和成年条件性DNMT 1野生型和敲除小鼠进行全面的表型表征。此外，迁移SST-中间神经元中DNA甲基化的DNMT 1依赖性重构将通过基于FACS富集的SST中间神经元的测序分析来揭示，以绘制Dnmt 1缺失后DNA甲基化和转录的全局变化。解码SST中间神经元在其成熟期间采用的DNMT 1依赖性表观遗传重构有助于更好地理解亚型特异性发育程序，并且可能与疾病相关的问题有关。为建立基于表观遗传学的疗法开辟了新的途径。

The spatial and temporal inhibitory actions of the enormously heterogeneously collection of GABAergic interneurons tremendously influence cortical information processing, which is reflected by diseases like autism, epilepsy and schizophrenia that involve defective cortical inhibition. Decrypting regulatory networks that direct subtype-specific cortical interneuron development is of great interest, as this helps to identify critical events implicated in the etiology of such diseases. Epigenetic mechanisms of gene regulation like DNA methylation executed by DNA methyltransferases (DNMTs) and histone modifications call increasing attention in sculpting developmental processes and human health. Several studies associate altered expression levels and function of the DNA methyltransferase 1 (DNMT1) in subsets of embryonic and adult cortical interneurons in patients diagnosed with schizophrenia. Although accumulating evidence supports the relevance of epigenetic signatures for instructing cell type-specific development, only very little is known about their functional implications in discrete developmental processes and in subtype-specific maturation of cortical interneurons.By single cell transcriptomics, global transcriptome and methylome analysis of FAC-sorted embryonic interneurons in combination with functional validation experiments, we have recently found that DNMT1 promotes the migration of interneurons originating in the preoptic area (POA) mainly through interactions with histone modifications.In contrast, preliminary experiments indicate that DNA methylating actions of DNMT1 seem crucial for the proper development of SST-positive interneurons, potentially involved in setting up transcriptional programs that direct the subtype-specific development. SST-interneurons are generated mainly in the MGE and have been shown to be affected in schizophrenia and in other human psychiatric and neurological disorders. Thus, we here aim to dissect the role of DNMT1 in the post-mitotic maturation of SST-positive interneurons. To this end, we will apply an innovative and diverse yet well-established collection of methods involving mouse genetics, high-throughput sequencing and functional bioassays. To determine the processes DNMT1 regulates during SST-interneuron maturation, a comprehensive phenotypic characterization of embryonic, postnatal and adult conditional DNMT1 wild-type and knockout mice will be conducted. Moreover, DNMT1-dependent remodeling in DNA methylation in migrating SST-interneurons will be revealed by sequencing-based analysis of FACS-enriched SST interneurons to map the global changes in DNA methylation and transcription upon Dnmt1 deletion.Decoding the DNMT1-dependent epigenetic reconfigurations SST interneurons adopt during their maturation helps to better understand subtype-specific developmental programs and might be of relevance for disease-related questions, opening new avenues for the establishment of epigenetic-based therapies.