DCAF13 promotes pluripotency by negatively regulating SUV39H1 stability during early embryonic development

• Published in: The EMBO journal 2018-09, Vol.37 (18), p.n/a
• Main Authors: Zhang, Yin‐Li, Zhao, Long‐Wen, Zhang, Jue, Le, Rongrong, Ji, Shu‐Yan, Chen, Chuan, Gao, Yawei, Li, Dali, Gao, Shaorong, Fan, Heng‐Yu
• Format: Article
• Language: English
• Subjects: Adapters; Animals; Blastocyst - cytology; Blastocyst - metabolism; Clonal deletion; Degradation; EMBO09; EMBO11; EMBO39; Embryogenesis; Embryonic Development; Embryonic growth stage; Embryos; Enzyme Stability; Fertility; Gametocytes; Gene expression; Gene Expression Regulation, Developmental; Genomes; Histone H3; histone methylation; Histones; Histones - genetics; Histones - metabolism; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Inhibitory postsynaptic potentials; Lethality; Lysine; maternal–zygotic transition; Methyltransferase; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Mice, Inbred ICR; Mice, Knockout; Nuclei (cytology); Oocytes; Oocytes - cytology; Oocytes - metabolism; Pluripotency; preimplantation embryos; Proteasomes; protein ubiquitination; Proteolysis; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Stem cell transplantation; Stem cells; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligase Complexes - genetics; Ubiquitin-Protein Ligase Complexes - metabolism; Ubiquitination - genetics; zygote; Zygotes
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201898981

Mammalian oocytes and zygotes have the unique ability to reprogram a somatic cell nucleus into a totipotent state. SUV39H1/2‐mediated histone H3 lysine‐9 trimethylation (H3K9me3) is a major barrier to efficient reprogramming. How SUV39H1/2 activities are regulated in early embryos and during generation of induced pluripotent stem cells (iPSCs) remains unclear. Since expression of the CRL4 E3 ubiquitin ligase in oocytes is crucial for female fertility, we analyzed putative CRL4 adaptors (DCAFs) and identified DCAF13 as a novel CRL4 adaptor that is essential for preimplantation embryonic development. Dcaf13 is expressed from eight‐cell to morula stages in both murine and human embryos, and Dcaf13 knockout in mice causes preimplantation‐stage mortality. Dcaf13 knockout embryos are arrested at the eight‐ to sixteen‐cell stage before compaction, and this arrest is accompanied by high levels of H3K9me3. Mechanistically, CRL4‐DCAF13 targets SUV39H1 for polyubiquitination and proteasomal degradation and therefore facilitates H3K9me3 removal and zygotic gene expression. Taken together, CRL4‐DCAF13‐mediated SUV39H1 degradation is an essential step for progressive genome reprogramming during preimplantation embryonic development. Synopsis DCAF13 is a novel CRL4 E3 ubiquitin ligase adaptor that prevents histone modification by the SUV39H1 methyltransferase, thereby allowing preimplantation embryonic development. DCAF13 is a bona fide CRL4 E3 ligase adaptor highly expressed in preimplantation‐stage embryos. DCAF13 mouse knockout causes embryonic lethality at the morula stage. CRL4‐DCAF13 mediates SUV39H1 polyubiquitination and proteasomal degradation. DCAF13 deletion inhibits removal of histone H3‐Lys9 trimethylation marks, thereby inhibiting zygotic gene expression. Graphical Abstract DCAF13 is a novel CRL4 ubiquitin ligase adaptor that is essential for early embryonic nuclear reprogramming.