Proteogenomic reprogramming to a functional human blastomere-like stem cell state via a PARP-DUX4 regulatory axis
Ludovic Zimmerlin,
Ariana Angarita,
Tea Soon Park,
Rebecca Evans-Moses,
Justin Thomas,
Sirui Yan,
Isabel Uribe,
Isabella Vegas,
Clara Kochendoerfer,
Willem Buys,
Anthony K.L. Leung,
Elias T. Zambidis
Affiliations
Ludovic Zimmerlin
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Ariana Angarita
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Tea Soon Park
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Rebecca Evans-Moses
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Justin Thomas
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Sirui Yan
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Isabel Uribe
Departments of Biochemistry and Molecular Biology, The Johns Hopkins School of Public Health, Baltimore, MD, USA
Isabella Vegas
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Clara Kochendoerfer
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Willem Buys
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
Anthony K.L. Leung
Departments of Biochemistry and Molecular Biology, The Johns Hopkins School of Public Health, Baltimore, MD, USA
Elias T. Zambidis
Institute for Cell Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA; Corresponding author
Summary: Here, we show that conventional human pluripotent stem cells cultured with non-specific tankyrase-PARP1-inhibited conditions underwent proteogenomic reprogramming to functional blastomere-like tankyrase/PARP inhibitor-regulated naive stem cells (TIRN-SC). TIRN-SCs concurrently expressed hundreds of pioneer factors in hybrid 2C-8C-morula-ICM programs that were augmented by induced expression of DUX4. Injection of TIRN-SCs into 8C-staged murine embryos equipotently differentiated human cells to the extra-embryonic and embryonic compartments of chimeric blastocysts and fetuses. Ectopic expression of murine-E-Cadherin in TIRN-SCs further enhanced interspecific chimeric tissue targeting. TIRN-SC-derived trophoblast stem cells efficiently generated placental chimeras. Proteome-ubiquitinome analyses revealed increased TNKS and reduced PARP1 levels and an ADP-ribosylation-deficient, hyper-ubiquitinated proteome that impacted expression of both tankyrase and PARP1 substrates. ChIP-seq of NANOG-SOX2-OCT4 and PARP1 (NSOP) revealed genome-wide NSOP co-binding at DUX4-accessible enhancers of embryonic lineage factors; suggesting a DUX4-NSOP axis regulated TIRN-SC lineage plasticity. TIRN-SCs may serve as valuable models for studying the proteogenomic regulation of pre-lineage human embryogenesis. Video abstract:
