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

By A. Fütterer, Jésus de Celis, R. Navajas, L. Almonacid, J. Gutiérrez, Amaia Talavera-Gutiérrez, Cristina Pacios-Bras, Ilenia Bernascone, F. Martín‐Belmonte, Carlos Martínez-A. 2017

26 citations recorded by the source corpus.

Summary 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.

Subfields: Molecular Biology

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Citations in the corpus

Interplay between splicing and transcriptional pausing exerts genome-wide control over alternative polyadenylation (2021, methodology): “CHIP-seq data for DIDO3 (PRJNA33599) were published before [24].”
Dido3-dependent SFPQ recruitment maintains efficiency in mammalian alternative splicing (2019, background): “Previous attempts to generate constitutive mutants without Dido3 resulted in an embryonic lethal phenotype (30,52).”