Transient Partial Inhibition of DNA Polymerase α Promotes Chromatin Plasticity and Enhances Human Cell Reprogramming
- 1HHMI, Johns Hopkins University
Abstract
Somatic cell reprogramming requires extensive remodeling of epigenomic and transcriptional state, yet the mechanisms that enhance chromatin plasticity during cell-fate conversion remain incompletely understood. Beyond its essential role in genome duplication, DNA replication provides a dynamic window for chromatin remodeling and may therefore influence cellular plasticity during reprogramming. Here, we show that low-dose, transient inhibition of the lagging-strand DNA polymerase (Pol ) complex markedly enhances reprogramming of human peripheral blood mononuclear cells into induced pluripotent stem cells (iPSCs). Fine-tuned inhibition of the catalytic subunit PolA1 increases cell survival under reprogramming-associated stress and enhances cellular resilience to diverse external stresses, preserves genomic stability, and accelerates the acquisition of pluripotent features. PolA1-inhibited cells undergo rapid increases in chromatin accessibility following reprogramming factor delivery and display accelerated progression toward the iPSC state. Consistent with enhanced developmental plasticity, colonies derived from PolA1 inhibitor-treatment display dome-shaped morphology, increased expression of several naive pluripotency markers such as SUSD2. Integrated imaging and single-nucleus multiomic analyses establish transient PolA1 inhibition as a potent regulator of early chromatin remodeling during reprogramming. Functionally, PolA1 inhibitor-derived iPSC lines maintain stable pluripotency and exhibit enhanced differentiation potential, including increased embryoid body budding and accelerated cardiomyocyte differentiation and maturation. Notably, transient and low-dose PolA1 inhibition alters replication-coupled histone incorporation without reducing DNA replication speed or affecting cell cycle progression. This two-step regime primes human PBMCs for sustained gains in reprogramming efficiency with pre- and post-treatment. Together, these findings identify replication-coupled chromatin regulation as an underappreciated mechanism regulating human cell fate plasticity and demonstrate that transient modulation of Pol can simultaneously enhance epigenomic plasticity and preserve genome stability during reprogramming.
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BibTeX
@misc{chen2026transient,
title = {{Transient Partial Inhibition of DNA Polymerase α Promotes Chromatin Plasticity and Enhances Human Cell Reprogramming}},
author = {X. Chen and J. Q. Luo and Y. Yang and G. Yang and R. Lee and B. Ma},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.25.761701},
url = {https://www.biorxiv.org/content/10.64898/2026.10.25.761701v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Transient Partial Inhibition of DNA Polymerase α Promotes Chromatin Plasticity and Enhances Human Cell Reprogramming
AU - X. Chen
AU - J. Q. Luo
AU - Y. Yang
AU - G. Yang
AU - R. Lee
AU - B. Ma
PY - 2026
DA - 2026/10/25
PB - bioRxiv
DO - 10.64898/2026.10.25.761701
UR - https://www.biorxiv.org/content/10.64898/2026.10.25.761701v1
AB - Somatic cell reprogramming requires extensive remodeling of epigenomic and transcriptional state, yet the mechanisms that enhance chromatin plasticity during cell-fate conversion remain incompletely understood. Beyond its essential role in genome duplication, DNA replication provides a dynamic window for chromatin remodeling and may therefore influence cellular plasticity during reprogramming. Here, we show that low-dose, transient inhibition of the lagging-strand DNA polymerase (Pol ) complex markedly enhances reprogramming of human peripheral blood mononuclear cells into induced pluripotent stem cells (iPSCs). Fine-tuned inhibition of the catalytic subunit PolA1 increases cell survival under reprogramming-associated stress and enhances cellular resilience to diverse external stresses, preserves genomic stability, and accelerates the acquisition of pluripotent features. PolA1-inhibited cells undergo rapid increases in chromatin accessibility following reprogramming factor delivery and display accelerated progression toward the iPSC state. Consistent with enhanced developmental plasticity, colonies derived from PolA1 inhibitor-treatment display dome-shaped morphology, increased expression of several naive pluripotency markers such as SUSD2. Integrated imaging and single-nucleus multiomic analyses establish transient PolA1 inhibition as a potent regulator of early chromatin remodeling during reprogramming. Functionally, PolA1 inhibitor-derived iPSC lines maintain stable pluripotency and exhibit enhanced differentiation potential, including increased embryoid body budding and accelerated cardiomyocyte differentiation and maturation. Notably, transient and low-dose PolA1 inhibition alters replication-coupled histone incorporation without reducing DNA replication speed or affecting cell cycle progression. This two-step regime primes human PBMCs for sustained gains in reprogramming efficiency with pre- and post-treatment. Together, these findings identify replication-coupled chromatin regulation as an underappreciated mechanism regulating human cell fate plasticity and demonstrate that transient modulation of Pol can simultaneously enhance epigenomic plasticity and preserve genome stability during reprogramming.
ER -