Chavan Ankita, Isenhart Randi, Nguyen Son C, Kotb Noor, Harke Jailynn, Sintsova Anna, Ulukaya Gulay, Uliana Federico, Ashiono Caroline, Kutay Ulrike, Pegoraro Gianluca, Rangan Prashanth, Joyce Eric F, Jagannathan Madhav
Institute of Biochemistry, Department of Biology, ETH Zürich, Switzerland.
Bringing Materials to Life Consortium, ETH Zürich, Switzerland.
bioRxiv. 2023 Nov 17:2023.11.17.567611. doi: 10.1101/2023.11.17.567611.
The association of genomic loci to the nuclear periphery is proposed to facilitate cell-type specific gene repression and influence cell fate decisions. However, the interplay between gene position and expression remains incompletely understood, in part because the proteins that position genomic loci at the nuclear periphery remain unidentified. Here, we used an Oligopaint-based HiDRO screen targeting ~1000 genes to discover novel regulators of nuclear architecture in cells. We identified the heterochromatin-associated protein, Stonewall (Stwl), as a factor promoting perinuclear chromatin positioning. In female germline stem cells (GSCs), Stwl binds and positions chromatin loci, including GSC differentiation genes, at the nuclear periphery. Strikingly, Stwl-dependent perinuclear positioning is associated with transcriptional repression, highlighting a likely mechanism for Stwl's known role in GSC maintenance and ovary homeostasis. Thus, our study identifies perinuclear anchors in and demonstrates the importance of gene repression at the nuclear periphery for cell fate.
基因组位点与核周的关联被认为有助于细胞类型特异性的基因抑制并影响细胞命运决定。然而，基因位置与表达之间的相互作用仍未被完全理解，部分原因是将基因组位点定位到核周的蛋白质仍未被鉴定出来。在这里，我们使用了基于寡核苷酸原位杂交的高分辨率原位RNA成像（HiDRO）筛选技术，靶向约1000个基因，以发现细胞中核结构的新型调节因子。我们鉴定出异染色质相关蛋白斯通沃尔（Stwl）是促进核周染色质定位的一个因子。在雌性生殖系干细胞（GSC）中，Stwl结合并将染色质位点，包括GSC分化基因，定位在核周。引人注目的是，依赖Stwl的核周定位与转录抑制相关，这突出了Stwl在GSC维持和卵巢内稳态中已知作用的一种可能机制。因此，我们的研究确定了细胞中的核周锚定物，并证明了核周基因抑制对细胞命运的重要性。
