DIDO as a Switchboard that Regulates Self-Renewal and Differentiation in Embryonic Stem Cells.
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.
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
Agnes
A
Fütterer
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
Jésus
J
de Celis
Proteomics Unit, ProteoRed ISCIII, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
Rosana
R
Navajas
Genomics Unit, Q-PCR Facility, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
Luis
L
Almonacid
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
Julio
J
Gutiérrez
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
Amaia
A
Talavera-Gutiérrez
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
Cristina
C
Pacios-Bras
Department of Development and Differentiation, Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Ilenia
I
Bernascone
Department of Development and Differentiation, Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Fernando
F
Martin-Belmonte
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain. Electronic address: cmartineza@cnb.csic.es.
Carlos
C
Martinéz-A
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D016764:Cell Polarity; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D060066:Protein Interaction Maps; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D004268:DNA-Binding Proteins; C120687:Dido protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D020033:Protein Isoforms; D014157:Transcription Factors; C487995:Wwp2 protein, mouse; D044767:Ubiquitin-Protein Ligases
cell differentiation; cell polarization; primitive endoderm formation; stem cell self-renewal; transcriptional regulation