An Hdac1/Rpd3-Poised Circuit Balances Continual Self-Renewal and Rapid Restriction of Developmental Potential during Asymmetric Stem Cell Division.
An Hdac1/Rpd3-Poised Circuit Balances Continual Self-Renewal and Rapid Restriction of Developmental Potential during Asymmetric Stem Cell Division.
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DOI：
10.1016/j.devcel.2017.01.014
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发表时间：
2017-02-27
影响因子：
11.8
通讯作者：
Lee CY
中科院分区：
文献类型：
--
作者：
Janssens DH;Hamm DC;Anhezini L;Xiao Q;Siller KH;Siegrist SE;Harrison MM;Lee CY
不对称干细胞分裂后，分化干细胞后代的发育潜力如何迅速而稳定地受到限制尚不清楚。在果蝇幼虫大脑中，耳罩（erm）的独特功能是限制神经干细胞（神经母细胞）不对称分裂产生的中间神经祖细胞（INPs）的发育潜力。在这里，我们证明了组蛋白去乙酰化酶Hdac1/Rpd3与自我更新转录抑制因子一起作用，以维持神经母细胞中erm未成熟INP增强子处于非活性但平衡状态。在未成熟INP出生的两小时内，抑制因子活性的下调减轻了rpd3介导的对erm增强子的抑制，使多种组蛋白乙酰化并激活erm表达。Erm通过抑制编码神经母细胞转录激活因子的基因来限制未成熟INPs的发育潜力。我们提出，在干细胞中通过持续的组蛋白去乙酰化来激活分化主调控因子的快速激活增强子，可以实现不对称分裂后的自我更新和快速限制发育潜力。
How the developmental potential of differentiating stem cell progeny becomes rapidly and stably restricted following asymmetric stem cell division is unclear. In the fly larval brain, earmuff (erm) uniquely functions to restrict the developmental potential of intermediate neural progenitors (INPs) generated by asymmetrically dividing neural stem cells (neuroblasts). Here we demonstrate that the histone deacetylase Hdac1/Rpd3 functions together with self-renewal transcriptional repressors to maintain the erm immature INP enhancer in an inactive but poised state in neuroblasts. Within two-hours of immature INP birth, down-regulation of repressor activities alleviates Rpd3-mediated repression on the erm enhancer, enabling acetylation of multiple histone proteins and activating Erm expression. Erm restricts the developmental potential in immature INPs by repressing genes encoding neuroblast transcriptional activators. We propose that poising the fast-activating enhancers of master regulators of differentiation through continual histone deacetylation in stem cells enables self-renewal and rapid restriction of developmental potential following asymmetric division.