RT Journal Article
SR Electronic
T1 A Pluripotent Developmental State Confers a Low Fidelity of Chromosome Segregation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.03.01.482524
DO 10.1101/2022.03.01.482524
A1 Chenhui Deng
A1 Amanda Ya
A1 Duane A. Compton
A1 Kristina M. Godek
YR 2022
UL http://biorxiv.org/content/early/2022/03/01/2022.03.01.482524.abstract
AB Human pluripotent stem cells (hPSCs) frequently become aneuploid with abnormal chromosome numbers due to mitotic chromosome segregation errors during propagation in culture. Yet, we do not understand why hPSCs exhibit a low mitotic fidelity. Here we investigate the mechanisms responsible for mitotic errors in hPSCs and show that the primary cause is lagging chromosomes with improper merotelic chromosome microtubule attachments in anaphase. Accordingly, we can improve merotelic error correction and reduce lagging chromosome rates in hPSCs using small molecules that prolong mitotic duration or destabilize chromosome microtubule attachments providing chemical strategies to preserve genome stability. Strikingly, we also demonstrate that mitotic error rates correlate with developmental potential decreasing upon differentiation and loss of pluripotency and conversely increasing after reprogramming to a pluripotent state. Thus, chromosome segregation fidelity is inherently low in hPSCs and depends on developmental state in normal human cells.Competing Interest StatementThe authors have declared no competing interest.