Thymic T细胞发育在SATB1基因调控器的调控作用下进行。在本研究中，我们展示了SATB1参与转录和剪接的调控，并发现Satb1敲除小鼠胸腺细胞中，这两个过程均表现出失调。更重要的是，我们鉴定了一种新的SATB1蛋白异构体，并描述了其与常规研究的异构体在生物物理行为上的差异，暗示其可能存在功能差异。SATB1利用其类似朊病毒的结构域在液态状态和聚集体结构之间转变。这种行为取决于蛋白浓度、磷酸化和与核RNA的相互作用。值得注意的是，长SATB1异构体更容易在相分离后聚集。因此，对SATB1异构体表达水平的严格调控以及蛋白质翻译后修饰十分重要，它们是SATB1在T细胞发育中发挥作用的必要条件。我们的数据表明，这些过程的紊乱可能与癌症等疾病有关。版权所有© 2023 Zelenka, Papamatheakis, Tzerpos, Panagopoulos, Tsolis, Papadakis, Mariatos Metaxas, Papadogkonas, Mores, Kapsetaki, Papamatheakis, Stanek and Spilianakis.

Intra-thymic T cell development is coordinated by the regulatory actions of SATB1 genome organizer. In this report, we show that SATB1 is involved in the regulation of transcription and splicing, both of which displayed deregulation in Satb1 knockout murine thymocytes. More importantly, we characterized a novel SATB1 protein isoform and described its distinct biophysical behavior, implicating potential functional differences compared to the commonly studied isoform. SATB1 utilized its prion-like domains to transition through liquid-like states to aggregated structures. This behavior was dependent on protein concentration as well as phosphorylation and interaction with nuclear RNA. Notably, the long SATB1 isoform was more prone to aggregate following phase separation. Thus, the tight regulation of SATB1 isoforms expression levels alongside with protein post-translational modifications, are imperative for SATB1's mode of action in T cell development. Our data indicate that deregulation of these processes may also be linked to disorders such as cancer.Copyright © 2023 Zelenka, Papamatheakis, Tzerpos, Panagopoulos, Tsolis, Papadakis, Mariatos Metaxas, Papadogkonas, Mores, Kapsetaki, Papamatheakis, Stanek and Spilianakis.