Computational simulation of JAK/STAT signaling in somatic versus germline stem cells.
Computational simulation of JAK/STAT signaling in somatic versus germline stem cells.
复制标题
体细胞与生殖干细胞中 JAK/STAT 信号传导的计算模拟。
DOI：
10.1002/dvdy.684
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Li,WillisX
中科院分区：
文献类型：
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作者：
Li,WillisX
背景Janus激酶/信号转导和转录激活因子（JAK/STAT）信号通路调节多种细胞过程。该途径中的主要活化事件涉及STAT的酪氨酸的磷酸化，将未磷酸化的STAT（uSTAT）转化为磷酸化的STAT（pSTAT），一种活性转录因子。在一个非经典的作用，uSTAT有助于维持异染色质的稳定性。因此，pSTAT的增加同时也减少了uSTAT，导致异染色质丢失，如在果蝇体细胞组织中观察到的。有趣的是，相反的现象发生在果蝇生殖系干细胞（GSC）中，由于配体的持续供应，JAK/STAT通路保持持续活性。在这里，采用计算机模拟来剖析不同细胞背景下的JAK/STAT途径激活，模拟体细胞和生殖细胞。在这些模拟中，利用常微分方程复制JAK/STAT信号在不同的conditions.ResultsThe结果表明，瞬态配体刺激，典型的体细胞组织中的化学反应，导致瞬时减少uSTAT水平。相反，持续的配体刺激，GSC的利基的一个特征，导致uSTAT水平升高在equilibrium.ConclusionThe模拟表明，配体暴露的持续时间可以解释所观察到的相反的影响JAK/STAT激活对异染色质的体细胞与GSC。
BackgroundThe Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway regulates a variety of cellular processes. A major activation event in this pathway involves the phosphorylation of a tyrosine of STAT, converting unphosphorylated STAT (uSTAT) to phosphorylated STAT (pSTAT), an active transcription factor. In a noncanonical role, uSTAT contributes to the maintenance of heterochromatin stability. As such, an increase in pSTAT concurrently reduces uSTAT, resulting in heterochromatin loss, as observed inDrosophilasomatic tissues. Paradoxically, an opposing phenomenon occurs inDrosophilamale germline stem cells (GSCs), where the JAK/STAT pathway remains persistently active due to a continuous supply of ligands. Here, computational simulations were employed to dissect JAK/STAT pathway activation under different cellular contexts, mimicking somatic and germline cells. In these simulations, ordinary differential equations were leveraged to replicate the chemical reactions governing JAK/STAT signaling under different conditions.ResultsThe outcomes indicate that transient ligand stimulation, typical in somatic tissues, led to a momentary reduction in uSTAT levels. Conversely, sustained ligand stimulation, a characteristic feature of the GSC niche, resulted in elevated uSTAT levels at equilibrium.ConclusionThe simulation suggests that the duration of ligand exposure could explain the observed opposite effects of JAK/STAT activation on heterochromatin in somatic versus GSCs.