Disabling leading and lagging strand histone transmission results in parental histones loss and reduced cell plasticity and viability

Leonie Kollenstart; Alva Biran; Nicolas Alcaraz; Nazaret Reverón-Gómez; Victor Solis-Mezarino; Moritz Völker-Albert; Fion Jenkinson; Valentin Flury; Anja Groth

doi:10.1126/sciadv.adr1453

Disabling leading and lagging strand histone transmission results in parental histones loss and reduced cell plasticity and viability

Leonie Kollenstart, Alva Biran, Nicolas Alcaraz, Nazaret Reverón-Gómez, Victor Solis-Mezarino, Moritz Völker-Albert, Fion Jenkinson, Valentin Flury, Anja Groth^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

2 Downloads (Pure)

Abstract

In the process of DNA replication, the first steps in restoring the chromatin landscape involve parental histone recycling and new histone deposition. Disrupting histone recycling to either the leading or lagging strand induces asymmetric histone inheritance, affecting epigenome maintenance and cellular identity. However, the order and kinetics of these effects remain elusive. Here, we use inducible mutants to dissect the early and late consequences of impaired histone recycling. Simultaneous disruption of both leading (POLE4) and lagging strand (MCM2-2A) recycling pathways impairs the transmission of parental histones to newly synthesized DNA, releasing some parental histones to the soluble pool. Subsequently, H3K27me3 accumulates aberrantly during chromatin restoration in a manner preceding gene expression changes. Loss of histone inheritance and the ensuing chromatin restoration defects alter gene expression in embryonic stem cells and challenge differentiation programs and cell viability. Our findings demonstrate the importance of efficient transmission of histone-based information during DNA replication for maintaining chromatin landscapes, differentiation potential, and cellular viability.

Originalsprog	Engelsk
Artikelnummer	eadr1453
Tidsskrift	Science Advances
Vol/bind	11
Udgave nummer	8
Antal sider	15
ISSN	2375-2548
DOI	https://doi.org/10.1126/sciadv.adr1453
Status	Udgivet - 2025

Bibliografisk note

Funding Information:
We would like to thank the entire Groth laboratory for fruitful discussions, D. Mayer for discussion on the differentiation experiments, S. Boulton for sharing POLE4 antibodies, N. Mailand lab for sharing antibodies, M. Michaut, H. Wollmann, and A. Kalvisa from the CPR/ReNew Genomics Platform for technical support, support, and use of instruments, and G. de la Cruz and the reNEW Flow Cytometry Platform for technical expertise, support, and use of instruments. Research in the Groth lab is supported by The Lundbeck Foundation Post-doc fellowship R402-2022-1502 (F.J.), the European Research Council grant ERC CoG 724436 (A.G.), the Novo Nordisk Foundation NNF21OC0067425 (A.G.), the Novo Nordisk Foundation_ NNF23OC0086482 (A.G.), Independent Research Fund Denmark (Danmarks Frie Forskninsfond, DFF) 7079-00005B (A.G.), Danish Cancer Society KBVU-BK project R352-A20669 (A.G.), and Independent Research Fund Denmark (Danmarks Frie Forskninsfond, DFF) 3101-00149B (A.G.). Research at CPR is supported by the Novo Nordisk Foundation NNF14CC0001.

Publisher Copyright:
Copyright © 2025 The Authors, some rights reserved.

Adgang til dokumentet

10.1126/sciadv.adr1453Licens: CC BY

FulltextForlagets udgivne version, 3,13 MBLicens: CC BY

Citationsformater

@article{f7964bcf5d3641f88b079b9f8db013d4,

title = "Disabling leading and lagging strand histone transmission results in parental histones loss and reduced cell plasticity and viability",

abstract = "In the process of DNA replication, the first steps in restoring the chromatin landscape involve parental histone recycling and new histone deposition. Disrupting histone recycling to either the leading or lagging strand induces asymmetric histone inheritance, affecting epigenome maintenance and cellular identity. However, the order and kinetics of these effects remain elusive. Here, we use inducible mutants to dissect the early and late consequences of impaired histone recycling. Simultaneous disruption of both leading (POLE4) and lagging strand (MCM2-2A) recycling pathways impairs the transmission of parental histones to newly synthesized DNA, releasing some parental histones to the soluble pool. Subsequently, H3K27me3 accumulates aberrantly during chromatin restoration in a manner preceding gene expression changes. Loss of histone inheritance and the ensuing chromatin restoration defects alter gene expression in embryonic stem cells and challenge differentiation programs and cell viability. Our findings demonstrate the importance of efficient transmission of histone-based information during DNA replication for maintaining chromatin landscapes, differentiation potential, and cellular viability.",

author = "Leonie Kollenstart and Alva Biran and Nicolas Alcaraz and Nazaret Rever{\'o}n-G{\'o}mez and Victor Solis-Mezarino and Moritz V{\"o}lker-Albert and Fion Jenkinson and Valentin Flury and Anja Groth",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 The Authors, some rights reserved.",

year = "2025",

doi = "10.1126/sciadv.adr1453",

language = "English",

volume = "11",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "8",

}

TY - JOUR

T1 - Disabling leading and lagging strand histone transmission results in parental histones loss and reduced cell plasticity and viability

AU - Kollenstart, Leonie

AU - Biran, Alva

AU - Alcaraz, Nicolas

AU - Reverón-Gómez, Nazaret

AU - Solis-Mezarino, Victor

AU - Völker-Albert, Moritz

AU - Jenkinson, Fion

AU - Flury, Valentin

AU - Groth, Anja

PY - 2025

Y1 - 2025

N2 - In the process of DNA replication, the first steps in restoring the chromatin landscape involve parental histone recycling and new histone deposition. Disrupting histone recycling to either the leading or lagging strand induces asymmetric histone inheritance, affecting epigenome maintenance and cellular identity. However, the order and kinetics of these effects remain elusive. Here, we use inducible mutants to dissect the early and late consequences of impaired histone recycling. Simultaneous disruption of both leading (POLE4) and lagging strand (MCM2-2A) recycling pathways impairs the transmission of parental histones to newly synthesized DNA, releasing some parental histones to the soluble pool. Subsequently, H3K27me3 accumulates aberrantly during chromatin restoration in a manner preceding gene expression changes. Loss of histone inheritance and the ensuing chromatin restoration defects alter gene expression in embryonic stem cells and challenge differentiation programs and cell viability. Our findings demonstrate the importance of efficient transmission of histone-based information during DNA replication for maintaining chromatin landscapes, differentiation potential, and cellular viability.

AB - In the process of DNA replication, the first steps in restoring the chromatin landscape involve parental histone recycling and new histone deposition. Disrupting histone recycling to either the leading or lagging strand induces asymmetric histone inheritance, affecting epigenome maintenance and cellular identity. However, the order and kinetics of these effects remain elusive. Here, we use inducible mutants to dissect the early and late consequences of impaired histone recycling. Simultaneous disruption of both leading (POLE4) and lagging strand (MCM2-2A) recycling pathways impairs the transmission of parental histones to newly synthesized DNA, releasing some parental histones to the soluble pool. Subsequently, H3K27me3 accumulates aberrantly during chromatin restoration in a manner preceding gene expression changes. Loss of histone inheritance and the ensuing chromatin restoration defects alter gene expression in embryonic stem cells and challenge differentiation programs and cell viability. Our findings demonstrate the importance of efficient transmission of histone-based information during DNA replication for maintaining chromatin landscapes, differentiation potential, and cellular viability.

U2 - 10.1126/sciadv.adr1453

DO - 10.1126/sciadv.adr1453

M3 - Journal article

C2 - 39970210

AN - SCOPUS:85218339423

SN - 2375-2548

VL - 11

JO - Science Advances

JF - Science Advances

IS - 8

M1 - eadr1453

ER -