Transitions in cell potency during early mouse development are driven by Notch
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Spain
- Sloan Kettering Institute, United States
Abstract
The Notch signalling pathway plays fundamental roles in diverse developmental processes in metazoans, where it is important in driving cell fate and directing differentiation of various cell types. However, we still have limited knowledge about the role of Notch in early preimplantation stages of mammalian development, or how it interacts with other signalling pathways active at these stages such as Hippo. By using genetic and pharmacological tools in vivo, together with image analysis of single embryos and pluripotent cell culture, we have found that Notch is active from the 4-cell stage. Transcriptomic analysis in single morula identified novel Notch targets, such as early naïve pluripotency markers or transcriptional repressors such as TLE4. Our results reveal a previously undescribed role for Notch in driving transitions during the gradual loss of potency that takes place in the early mouse embryo prior to the first lineage decisions.
Data availability
Sequencing data have been deposited in GEO under accession code GSE121979.
-
Transitions in cell potency during early mouse development are driven by NotchNCBI Gene Expression Omnibus, GSE121979.
-
The landscape of accessible chromatin in mammalian pre-implantation embryosNCBI Gene Expression Omnibus, GSE66390.
Article and author information
Author details
Anna-Katerina Hadjantonakis
Funding
Ministerio de Economía y Competitividad (BFU2017-84914-P)
- Sergio Menchero
- Isabel Rollan
- Antonio Lopez-Izquierdo
- Maria Jose Andreu
- Julio Sainz de Aja
- Javier Adan
- Teresa Rayon
- Miguel Manzanares
ProCNIC Foundation
- Sergio Menchero
- Isabel Rollan
- Antonio Lopez-Izquierdo
- Maria Jose Andreu
- Julio Sainz de Aja
- Javier Adan
- Rui Benedito
- Teresa Rayon
- Miguel Manzanares
National Institutes of Health (NIH-R01DK084391)
- Minjung Kang
- Anna-Katerina Hadjantonakis
Ministerio de Economía y Competitividad (BFU2015-72319-EXP)
- Sergio Menchero
- Isabel Rollan
- Maria Jose Andreu
- Miguel Manzanares
Ministerio de Economía y Competitividad (SEV-2015-0505)
- Sergio Menchero
- Isabel Rollan
- Antonio Lopez-Izquierdo
- Maria Jose Andreu
- Julio Sainz de Aja
- Javier Adan
- Rui Benedito
- Teresa Rayon
- Miguel Manzanares
Ministerio de Economía y Competitividad (SVP-2013-067930)
- Sergio Menchero
National Institutes of Health (NIH-R01HD094868)
- Minjung Kang
- Anna-Katerina Hadjantonakis
National Institutes of Health (NIH-P30CA008748)
- Minjung Kang
- Anna-Katerina Hadjantonakis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with national and European Legislation. Procedures were approved by the CNIC Animal Welfare Ethics Committee and by the Area of Animal Protection of the Regional Government of Madrid (ref. PROEX 196/14).
Reviewing Editor
- Elizabeth Robertson, University of Oxford, United Kingdom
Publication history
- Received: October 17, 2018
- Accepted: April 7, 2019
- Accepted Manuscript published: April 8, 2019 (version 1)
- Version of Record published: April 26, 2019 (version 2)
Copyright
© 2019, Menchero et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,728
- Page views
-
- 594
- Downloads
-
- 23
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Transitions in cell potency during early mouse development are driven by Notch
eLife 8:e42930.
https://doi.org/10.7554/eLife.42930
Further reading
-
- Biochemistry and Chemical Biology
- Chromosomes and Gene Expression
In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation (e.g. K9ac, K14ac, K18ac) is linked to increased H3K4me3 engagement by the BPTF PHD finger, but it is unknown if this mechanism has a broader extension. Here, we show that H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and importantly, extends to H3K4 writers, notably methyltransferase MLL1. This regulation is not observed on peptide substrates yet occurs on the cis H3 tail, as determined with fully-defined heterotypic nucleosomes. In vivo, H3 tail acetylation is directly and dynamically coupled with cis H3K4 methylation levels. Together, these observations reveal an acetylation ‘chromatin switch’ on the H3 tail that modulates read-write accessibility in nucleosomes and resolves the long-standing question of why H3K4me3 levels are coupled with H3 acetylation.
-
- Chromosomes and Gene Expression
The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near-complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle and hyperactivity. This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health.
