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DIDO 作为调控胚胎干细胞自我更新和分化的总机。

DIDO as a Switchboard that Regulates Self-Renewal and Differentiation in Embryonic Stem Cells.

机构信息

Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.

Proteomics Unit, ProteoRed ISCIII, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.

出版信息

Stem Cell Reports. 2017 Apr 11;8(4):1062-1075. doi: 10.1016/j.stemcr.2017.02.013. Epub 2017 Mar 16.

DOI:10.1016/j.stemcr.2017.02.013
PMID:28330622
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5390109/
Abstract

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.

摘要

从对称细胞分裂到不对称细胞分裂的转变需要精确协调差异基因表达。我们表明胚胎干细胞（ESCs）主要表达 DIDO3，并且它们在白血病抑制因子撤出后的分化需要 DIDO1 表达。DIDO3 的 C 端截断（Dido3ΔCT）阻止 ESC 分化，同时保留自我更新；短发夹 RNA-Dido1 ESC 具有相同的表型。通过异位表达 DIDO3 可以挽救 Dido3ΔCT ESC 的分化，DIDO3 通过 H3K4me3 和 RNA POL II 结合 Dido 基因座，并诱导 DIDO1 表达。被运送到细胞质中的 DIDO1 与 PKCiota 结合，并被其 N 端磷酸化。它与 E3 泛素连接酶 WWP2 结合，通过 OCT4 降解促进细胞命运，从而允许原始内胚层（PE）标记的表达。PE 的形成还依赖于磷酸化 DIDO3 定位于中心体，这确保了它们的正确定位，以促进 PE 细胞极化。我们提出 DIDO 异构体作为一个开关，调节 ESC 从多能性维持到促进分化的遗传程序的转变。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/6cfb45648dc8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/61910b470bd9/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/5f84c7941b0a/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/2eb8d2abcb9a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/29320ddeca00/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/939b08aa52c5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/6cfb45648dc8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/61910b470bd9/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/5f84c7941b0a/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/2eb8d2abcb9a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/29320ddeca00/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/939b08aa52c5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe75/5390109/6cfb45648dc8/gr6.jpg

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