Proteogenomic reprogramming to a functional human blastomere-like stem cell state via a PARP-DUX4 regulatory axis
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. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
| Authors | Zimmerlin L, Angarita A, Park TS, Evans-Moses R, Thomas J, Yan S, Uribe I, Vegas I, Kochendoerfer C, Buys W, Leung AKL, Zambidis ET |
|---|---|
| Journal | Cell reports |
| Publication Date | 2025 May 27;44(5):115671 |
| PubMed | 40338744 |
| PubMed Central | PMC12541798 |
| DOI | 10.1016/j.celrep.2025.115671 |