DIDO as a Switchboard that Regulates Self-Renewal and Differentiation in Embryonic Stem Cells.
DIDO as a Switchboard that Regulates Self-Renewal and Differentiation in Embryonic Stem Cells.
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DOI：
10.1016/j.stemcr.2017.02.013
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发表时间：
2017-04-11
影响因子：
5.9
通讯作者：
Martinéz-A C
中科院分区：
文献类型：
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作者：
Fütterer A;de Celis J;Navajas R;Almonacid L;Gutiérrez J;Talavera-Gutiérrez A;Pacios-Bras C;Bernascone I;Martin-Belmonte F;Martinéz-A C
从对称到不对称的细胞分裂需要精确的基因表达协调。我们发现胚胎干细胞（ESCs）主要表达DIDO3，并且它们在白血病抑制因子停用后的分化需要DIDO1的表达。c端截断DIDO3 （Dido3ΔCT）阻碍ESC分化，同时保持自我更新；小发夹RNA-Dido1 ESCs具有相同的表型。Dido3ΔCT通过DIDO3异位表达挽救ESC分化，DIDO3通过H3K4me3和RNA POL II结合Dido位点，诱导DIDO1表达。DIDO1输出到细胞质，与PKCiota结合，并被PKCiota n端磷酸化。它结合E3泛素连接酶WWP2，通过OCT4降解促进细胞命运，从而允许原始内胚层（PE）标记物的表达。PE的形成还依赖于磷酸化的DIDO3在中心体上的定位，这保证了它们在PE细胞极化时的正确定位。我们提出DIDO异构体作为一个配电盘，调节ESC从多能性维持到促进分化的遗传程序。DIDO3调节DIDO1表达细胞质内DIDO1促进细胞命运DIDO3调节中心体位置DIDO1和DIDO3被PKCiota f<s:1> tterer等磷酸化表明DIDO1和DIDO3亚型调节ESCs的对称和不对称细胞分裂。DIDO3参与中心体定位使PE细胞极化，而DIDO1则决定它们的命运身份。此外，DIDO3在ESC分化开始时调控DIDO1的表达。
Transition from symmetric to asymmetric cell division requires precise coordination of differential gene expression. We show that embryonic stem cells (ESCs) mainly express DIDO3 and that their differentiation after leukemia inhibitory factor withdrawal requires DIDO1 expression. C-terminal truncation of DIDO3 (Dido3ΔCT) impedes ESC differentiation while retaining self-renewal; small hairpin RNA-Dido1 ESCs have the same phenotype. Dido3ΔCT ESC differentiation is rescued by ectopic expression of DIDO3, which binds the Dido locus via H3K4me3 and RNA POL II and induces DIDO1 expression. DIDO1, which is exported to cytoplasm, associates with, and is N-terminally phosphorylated by PKCiota. It binds the E3 ubiquitin ligase WWP2, which contributes to cell fate by OCT4 degradation, to allow expression of primitive endoderm (PE) markers. PE formation also depends on phosphorylated DIDO3 localization to centrosomes, which ensures their correct positioning for PE cell polarization. We propose that DIDO isoforms act as a switchboard that regulates genetic programs for ESC transition from pluripotency maintenance to promotion of differentiation. DIDO3 regulates DIDO1 expression Cytoplasmic DIDO1 promotes cell fate DIDO3 regulates centrosome position DIDO1 and DIDO3 are phosphorylated by PKCiota Fütterer et al. show that DIDO isoforms regulate symmetric and asymmetric cell division of ESCs. Whereas DIDO3 is involved in centrosome positioning to polarize PE cells, DIDO1 is determinant for their fate identity. Moreover, DIDO3 regulates DIDO1 expression at the onset of ESC differentiation.