Symmetric Inheritance of Parental Histones Governs Epigenome Maintenance and Embryonic Stem Cell Identity

Overview

Journal Nat Genet

Specialty Genetics

Date 2023 Sep 4

PMID 37666988

Authors

Alice Wenger

Alva Biran

Nicolas Alcaraz

Alba Redo-Riveiro

Annika Charlotte Sell

Robert Krautz

Valentin Flury

Nazaret Reveron-Gomez

Victor Solis-Mezarino

Moritz Volker-Albert

Axel Imhof

Robin Andersson

Joshua M Brickman

Anja Groth

Affiliations

Soon will be listed here.

Abstract

Modified parental histones are segregated symmetrically to daughter DNA strands during replication and can be inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here we show that transmission of histone-based information during DNA replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused derepression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Furthermore, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian cell differentiation.

Citing Articles

Increased levels of lagging strand polymerase α in an adult stem cell lineage affect replication-coupled histone incorporation.

Davis B, Snedeker J, Ranjan R, Wooten M, Barton S, Blundon J Sci Adv. 2025; 11(9):eadu6799.

PMID: 40020063 PMC: 11870066. DOI: 10.1126/sciadv.adu6799.

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

Kollenstart L, Biran A, Alcaraz N, Reveron-Gomez N, Solis-Mezarino V, Volker-Albert M Sci Adv. 2025; 11(8):eadr1453.

PMID: 39970210 PMC: 11837984. DOI: 10.1126/sciadv.adr1453.

A tale of two strands: Decoding chromatin replication through strand-specific sequencing.

Li Z, Zhang Z Mol Cell. 2025; 85(2):238-261.

PMID: 39824166 PMC: 11750172. DOI: 10.1016/j.molcel.2024.10.035.

Origin, fate and function of extraembryonic tissues during mammalian development.

Thowfeequ S, Hanna C, Srinivas S Nat Rev Mol Cell Biol. 2024; .

PMID: 39627419 DOI: 10.1038/s41580-024-00809-w.

Theory of epigenetic switching due to stochastic histone mark loss during DNA replication.

Movilla Miangolarra A, Howard M Phys Biol. 2024; 22(1).

PMID: 39556945 PMC: 11605279. DOI: 10.1088/1478-3975/ad942c.

References

Cantone I, Fisher A . Epigenetic programming and reprogramming during development. Nat Struct Mol Biol. 2013; 20(3):282-9. DOI: 10.1038/nsmb.2489. View

Iwafuchi-Doi M, Zaret K . Cell fate control by pioneer transcription factors. Development. 2016; 143(11):1833-7. PMC: 6514407. DOI: 10.1242/dev.133900. View

Yadav T, Quivy J, Almouzni G . Chromatin plasticity: A versatile landscape that underlies cell fate and identity. Science. 2018; 361(6409):1332-1336. DOI: 10.1126/science.aat8950. View

Morgani S, Nichols J, Hadjantonakis A . The many faces of Pluripotency: in vitro adaptations of a continuum of in vivo states. BMC Dev Biol. 2017; 17(1):7. PMC: 5470286. DOI: 10.1186/s12861-017-0150-4. View

Allis C, Jenuwein T . The molecular hallmarks of epigenetic control. Nat Rev Genet. 2016; 17(8):487-500. DOI: 10.1038/nrg.2016.59. View

Allshire R, Madhani H . Ten principles of heterochromatin formation and function. Nat Rev Mol Cell Biol. 2017; 19(4):229-244. PMC: 6822695. DOI: 10.1038/nrm.2017.119. View

Reinberg D, Vales L . Chromatin domains rich in inheritance. Science. 2018; 361(6397):33-34. DOI: 10.1126/science.aat7871. View

Stewart-Morgan K, Petryk N, Groth A . Chromatin replication and epigenetic cell memory. Nat Cell Biol. 2020; 22(4):361-371. DOI: 10.1038/s41556-020-0487-y. View

Escobar T, Loyola A, Reinberg D . Parental nucleosome segregation and the inheritance of cellular identity. Nat Rev Genet. 2021; 22(6):379-392. PMC: 8609916. DOI: 10.1038/s41576-020-00312-w. View

10.

Reveron-Gomez N, Gonzalez-Aguilera C, Stewart-Morgan K, Petryk N, Flury V, Graziano S . Accurate Recycling of Parental Histones Reproduces the Histone Modification Landscape during DNA Replication. Mol Cell. 2018; 72(2):239-249.e5. PMC: 6202308. DOI: 10.1016/j.molcel.2018.08.010. View

11.

Schlissel G, Rine J . The nucleosome core particle remembers its position through DNA replication and RNA transcription. Proc Natl Acad Sci U S A. 2019; 116(41):20605-20611. PMC: 6789558. DOI: 10.1073/pnas.1911943116. View

12.

Escobar T, Oksuz O, Saldana-Meyer R, Descostes N, Bonasio R, Reinberg D . Active and Repressed Chromatin Domains Exhibit Distinct Nucleosome Segregation during DNA Replication. Cell. 2019; 179(4):953-963.e11. PMC: 6917041. DOI: 10.1016/j.cell.2019.10.009. View

13.

Gan H, Serra-Cardona A, Hua X, Zhou H, Labib K, Yu C . The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands. Mol Cell. 2018; 72(1):140-151.e3. PMC: 6193272. DOI: 10.1016/j.molcel.2018.09.001. View

14.

Petryk N, Dalby M, Wenger A, Stromme C, Strandsby A, Andersson R . MCM2 promotes symmetric inheritance of modified histones during DNA replication. Science. 2018; 361(6409):1389-1392. DOI: 10.1126/science.aau0294. View

15.

Yu C, Gan H, Serra-Cardona A, Zhang L, Gan S, Sharma S . A mechanism for preventing asymmetric histone segregation onto replicating DNA strands. Science. 2018; 361(6409):1386-1389. PMC: 6597248. DOI: 10.1126/science.aat8849. View

16.

Li Z, Hua X, Serra-Cardona A, Xu X, Gan S, Zhou H . DNA polymerase α interacts with H3-H4 and facilitates the transfer of parental histones to lagging strands. Sci Adv. 2020; 6(35):eabb5820. PMC: 7449674. DOI: 10.1126/sciadv.abb5820. View

17.

Alabert C, Barth T, Reveron-Gomez N, Sidoli S, Schmidt A, Jensen O . Two distinct modes for propagation of histone PTMs across the cell cycle. Genes Dev. 2015; 29(6):585-90. PMC: 4378191. DOI: 10.1101/gad.256354.114. View

18.

Zhang T, Cooper S, Brockdorff N . The interplay of histone modifications - writers that read. EMBO Rep. 2015; 16(11):1467-81. PMC: 4641500. DOI: 10.15252/embr.201540945. View

19.

Alabert C, Loos C, Voelker-Albert M, Graziano S, Forne I, Reveron-Gomez N . Domain Model Explains Propagation Dynamics and Stability of Histone H3K27 and H3K36 Methylation Landscapes. Cell Rep. 2020; 30(4):1223-1234.e8. DOI: 10.1016/j.celrep.2019.12.060. View

20.

Audergon P, Catania S, Kagansky A, Tong P, Shukla M, Pidoux A . Epigenetics. Restricted epigenetic inheritance of H3K9 methylation. Science. 2015; 348(6230):132-5. PMC: 4397586. DOI: 10.1126/science.1260638. View