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Developmental differences in genome replication program and origin activation.

Rausch, Cathia ; Weber, Patrick ; Prorok, Paulina ; Hörl, David ; Maiser, Andreas ; Lehmkuhl, Anne ; Chagin, Vadim O. ; Casas-Delucchi, Corella S. ; Leonhardt, Heinrich ; Cardoso, M. Cristina (2020):
Developmental differences in genome replication program and origin activation.
In: Nucleic acids research, 48 (22), pp. 12751-12777. ISSN 1362-4962,
DOI: 10.1093/nar/gkaa1124,
[Article]

Abstract

To ensure error-free duplication of all (epi)genetic information once per cell cycle, DNA replication follows a cell type and developmental stage specific spatio-temporal program. Here, we analyze the spatio-temporal DNA replication progression in (un)differentiated mouse embryonic stem (mES) cells. Whereas telomeres replicate throughout S-phase, we observe mid S-phase replication of (peri)centromeric heterochromatin in mES cells, which switches to late S-phase replication upon differentiation. This replication timing reversal correlates with and depends on an increase in condensation and a decrease in acetylation of chromatin. We further find synchronous duplication of the Y chromosome, marking the end of S-phase, irrespectively of the pluripotency state. Using a combination of single-molecule and super-resolution microscopy, we measure molecular properties of the mES cell replicon, the number of replication foci active in parallel and their spatial clustering. We conclude that each replication nanofocus in mES cells corresponds to an individual replicon, with up to one quarter representing unidirectional forks. Furthermore, with molecular combing and genome-wide origin mapping analyses, we find that mES cells activate twice as many origins spaced at half the distance than somatic cells. Altogether, our results highlight fundamental developmental differences on progression of genome replication and origin activation in pluripotent cells.

Item Type: Article
Erschienen: 2020
Creators: Rausch, Cathia ; Weber, Patrick ; Prorok, Paulina ; Hörl, David ; Maiser, Andreas ; Lehmkuhl, Anne ; Chagin, Vadim O. ; Casas-Delucchi, Corella S. ; Leonhardt, Heinrich ; Cardoso, M. Cristina
Title: Developmental differences in genome replication program and origin activation.
Language: English
Abstract:

To ensure error-free duplication of all (epi)genetic information once per cell cycle, DNA replication follows a cell type and developmental stage specific spatio-temporal program. Here, we analyze the spatio-temporal DNA replication progression in (un)differentiated mouse embryonic stem (mES) cells. Whereas telomeres replicate throughout S-phase, we observe mid S-phase replication of (peri)centromeric heterochromatin in mES cells, which switches to late S-phase replication upon differentiation. This replication timing reversal correlates with and depends on an increase in condensation and a decrease in acetylation of chromatin. We further find synchronous duplication of the Y chromosome, marking the end of S-phase, irrespectively of the pluripotency state. Using a combination of single-molecule and super-resolution microscopy, we measure molecular properties of the mES cell replicon, the number of replication foci active in parallel and their spatial clustering. We conclude that each replication nanofocus in mES cells corresponds to an individual replicon, with up to one quarter representing unidirectional forks. Furthermore, with molecular combing and genome-wide origin mapping analyses, we find that mES cells activate twice as many origins spaced at half the distance than somatic cells. Altogether, our results highlight fundamental developmental differences on progression of genome replication and origin activation in pluripotent cells.

Journal or Publication Title: Nucleic acids research
Journal Volume: 48
Issue Number: 22
Divisions: 10 Department of Biology
10 Department of Biology > Cell Biology and Epigenetics
Date Deposited: 08 Dec 2020 07:34
DOI: 10.1093/nar/gkaa1124
Identification Number: pmid:33264404
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