Department of Brain Sciences, DGIST, Daegu, 42988, Republic of Korea.
Department of New Biology, DGIST, Daegu, 42988, Republic of Korea.
Exp Mol Med. 2024 Feb;56(2):422-440. doi: 10.1038/s12276-024-01169-3. Epub 2024 Feb 19.
Accumulating evidence hints heterochromatin anchoring to the inner nuclear membrane as an upstream regulatory process of gene expression. Given that the formation of neural progenitor cell lineages and the subsequent maintenance of postmitotic neuronal cell identity critically rely on transcriptional regulation, it seems possible that the development of neuronal cells is influenced by cell type-specific and/or context-dependent programmed regulation of heterochromatin anchoring. Here, we explored this possibility by genetically disrupting the evolutionarily conserved barrier-to-autointegration factor (Baf) in the Drosophila nervous system. Through single-cell RNA sequencing, we demonstrated that Baf knockdown induces prominent transcriptomic changes, particularly in type I neuroblasts. Among the differentially expressed genes, our genetic analyses identified teashirt (tsh), a transcription factor that interacts with beta-catenin, to be closely associated with Baf knockdown-induced phenotypes that were suppressed by the overexpression of tsh or beta-catenin. We also found that Baf and tsh colocalized in a region adjacent to heterochromatin in type I NBs. Notably, the subnuclear localization pattern remained unchanged when one of these two proteins was knocked down, indicating that both proteins contribute to the anchoring of heterochromatin to the inner nuclear membrane. Overall, this study reveals that the Baf-mediated transcriptional regulation of teashirt is a novel molecular mechanism that regulates the development of neural progenitor cell lineages.
越来越多的证据表明，异染色质锚定在内核膜上是基因表达的上游调控过程。鉴于神经祖细胞谱系的形成以及随后的有丝分裂后神经元细胞身份的维持严重依赖于转录调控，异染色质锚定的细胞类型特异性和/或上下文依赖性程序化调控可能影响神经元细胞的发育。在这里，我们通过在果蝇神经系统中遗传破坏进化上保守的整合障碍因子（Baf）来探索这种可能性。通过单细胞 RNA 测序，我们证明 Baf 敲低诱导了显著的转录组变化，特别是在 I 型神经母细胞中。在差异表达的基因中，我们的遗传分析确定了与 Baf 敲低诱导表型密切相关的转录因子 teashirt（tsh），该表型可被 tsh 或 beta-catenin 的过表达抑制。我们还发现 Baf 和 tsh 在 I 型 NB 中异染色质附近的一个区域共定位。值得注意的是，当这两种蛋白质中的一种被敲低时，亚核定位模式保持不变，这表明这两种蛋白质都有助于将异染色质锚定在内核膜上。总的来说，这项研究揭示了 Baf 介导的 teashirt 的转录调控是调节神经祖细胞谱系发育的新分子机制。
