Obliterating Obstacles to an Odyssey
| Autor: | Kyle M. Loh, Massimo Nichane |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell type Induced Pluripotent Stem Cells Cell Gene Expression Cell Biology Biology Histone Deacetylases Article Cell biology 03 medical and health sciences 030104 developmental biology medicine.anatomical_structure Gene expression Genetics medicine Molecular Medicine Stem cell Induced pluripotent stem cell Corepressor Reprogramming Mi-2 Nucleosome Remodeling and Deacetylase Complex |
| Zdroj: | Cell Stem Cell |
| ISSN: | 1934-5909 |
| Popis: | Mbd3, a member of Nucleosome Remodeling and Deacetylase (NuRD) co-repressor complex, was previously identified as an inhibitor for deterministic iPSC reprogramming where up to 100% of donor cells successfully complete the process. NuRD can assume multiple mutually-exclusive conformations, and it remains unclear whether this deterministic phenotype can be attributed to a specific Mbd3/NuRD sub-complex. Moreover, since complete ablation of Mbd3 blocks somatic cell proliferation, we aimed to explore functionally relevant alternative ways to neutralize Mbd3-dependent NuRD activity. We identify Gatad2a, a NuRD-specific subunit, whose complete deletion specifically disrupts Mbd3/NuRD repressive activity on the pluripotency circuitry during iPSC differentiation and reprogramming without disrupting somatic cell proliferation. Ablation of Gatad2a facilitates deterministic murine iPSC reprogramming within 8-days. We validate a distinct molecular axis, Gatad2a-Chd4-Mbd3, within Mbd3/NuRD as being critical for blocking re-establishment of naïve pluripotency, and further highlight signaling-dependent and post-translational modifications of Mbd3/NuRD that influence its interactions and assembly. |
| Databáze: | OpenAIRE |
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