Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching.
Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching.
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MAP3K4、CBP 和 HDAC6 对 Rel 表达的协调调节控制着表型转换。
DOI：
10.1038/s42003-020-01200-z
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发表时间：
2020
影响因子：
5.9
通讯作者：
Abell,AmyNoel
中科院分区：
文献类型：
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作者：
Shendy,NohaAhmedMohammed;Raghu,Deepthi;Roy,Sujoy;Perry,CharlesHamilton;Safi,Adiba;Branco,MiguelRamos;Homayouni,Ramin;Abell,AmyNoel
在正常发育和疾病状态下，上皮和间充质表型之间的表型转换需要协调的基因表达。滋养层干细胞在着床和胎盘形成过程中经历上皮间充质转化(EMT)。在这些过程中协调基因表达的机制还知之甚少。我们先前已经证明，在TS细胞的EMT过程中，MAP3K4调节的染色质修饰物CBP和HDAC6各自调节数千个基因。在这里，我们表明CBP和HDAC6只协调183个基因的表达，这些基因被预测为表型转换的关键调节因子。最高级别的共同调控基因是NF-κB家族成员Rel。虽然NF-κB主要是转录后调节的，但CBP和HDAC6通过结合重新调节区和控制组蛋白乙酰化来控制REL转录水平。Rel在间充质样TS细胞中的重新表达可诱导间充质-上皮细胞的转变。重要的是，Rel形成一个反馈环，阻断HDAC6的表达和核定位。我们的工作共同定义了一个协调表型转换的发育计划。
Coordinated gene expression is required for phenotypic switching between epithelial and mesenchymal phenotypes during normal development and in disease states. Trophoblast stem (TS) cells undergo epithelial-mesenchymal transition (EMT) during implantation and placentation. Mechanisms coordinating gene expression during these processes are poorly understood. We have previously demonstrated that MAP3K4-regulated chromatin modifiers CBP and HDAC6 each regulate thousands of genes during EMT in TS cells. Here we show that CBP and HDAC6 coordinate expression of only 183 genes predicted to be critical regulators of phenotypic switching. The highest-ranking co-regulated gene is the NF-κB family memberRel. Although NF-κB is primarily regulated post-transcriptionally, CBP and HDAC6 control Rel transcript levels by bindingRelregulatory regions and controlling histone acetylation. REL re-expression in mesenchymal-like TS cells induces a mesenchymal-epithelial transition. Importantly, REL forms a feedback loop, blocking HDAC6 expression and nuclear localization. Together, our work defines a developmental program coordinating phenotypic switching.