Regulation of X-linked gene expression during early mouse development by Rlim
- University of Massachusetts Medical School, United States
- Massachusetts Institute of Technology, United States
- Broad Institute of MIT and Harvard, United States
Abstract
Mammalian X-linked gene expression is highly regulated as female cells contain two and male one X chromosome (X). To adjust the X gene dosage between genders, female mouse preimplantation embryos undergo an imprinted form of X chromosome inactivation (iXCI) that requires both Rlim (also known as Rnf12) and the long non-coding RNA Xist. Moreover, it is thought that gene expression from the single active X is upregulated to correct for bi-allelic autosomal (A) gene expression. We have combined mouse genetics with RNA-seq on single mouse embryos to investigate functions of Rlim on the temporal regulation of iXCI and Xist. Our results reveal crucial roles of Rlim for the maintenance of high Xist RNA levels, Xist clouds and X-silencing in female embryos at blastocyst stages, while initial Xist expression appears Rlim-independent. We find further that X/A upregulation is initiated in early male and female preimplantation embryos.
Data availability
-
Transcriptome of mouse preimplantation developmentPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE71442).
-
Single-cell RNA-Seq reveals dynamic, random monoallelic gene expression in mammalian cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE45719).
Article and author information
Author details
Funding
National Institutes of Health (R01CA131158)
- Ingolf Bach
National Institutes of Health (R01HD080224)
- Oliver J Rando
National Institutes of Health (DP1ES025458)
- Oliver J Rando
National Institutes of Health (R01GM053234)
- Jeanne B Lawrence
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kevin Struhl, Harvard Medical School, United States
Ethics
Animal experimentation: All mice were housed in the animal facility of UMMS, and utilized according to NIH guidelines and those established by the UMMS Institute of Animal Care and Usage Committee (IACUC protocol #: A-1940-14).
Version history
- Received: June 26, 2016
- Accepted: September 15, 2016
- Accepted Manuscript published: September 19, 2016 (version 1)
- Accepted Manuscript updated: September 20, 2016 (version 2)
- Accepted Manuscript updated: September 20, 2016 (version 3)
- Accepted Manuscript updated: September 20, 2016 (version 4)
- Version of Record published: October 11, 2016 (version 5)
Copyright
© 2016, Wang 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
-
- 2,407
- views
-
- 561
- downloads
-
- 35
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Regulation of X-linked gene expression during early mouse development by Rlim
eLife 5:e19127.
https://doi.org/10.7554/eLife.19127
Further reading
-
- Developmental Biology
We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibroblast growth factor (FGF) signaling in germ layer specification and head-to-tail development of Xenopus embryos. Here, we present an extracellular proteolytic mechanism involving this serpin-protease system in the developing neural crest (NC). Knockdown of SerpinE2 by injected antisense morpholino oligonucleotides did not affect the specification of NC progenitors but instead inhibited the migration of NC cells, causing defects in dorsal fin, melanocyte, and craniofacial cartilage formation. Similarly, overexpression of the HtrA1 protease impaired NC cell migration and the formation of NC-derived structures. The phenotype of SerpinE2 knockdown was overcome by concomitant downregulation of HtrA1, indicating that SerpinE2 stimulates NC migration by inhibiting endogenous HtrA1 activity. SerpinE2 binds to HtrA1, and the HtrA1 protease triggers degradation of the cell surface proteoglycan Syndecan-4 (Sdc4). Microinjection of Sdc4 mRNA partially rescued NC migration defects induced by both HtrA1 upregulation and SerpinE2 downregulation. These epistatic experiments suggest a proteolytic pathway by a double inhibition mechanism:
SerpinE2 ┤HtrA1 protease ┤Syndecan-4 → NC cell migration.
-
- Developmental Biology
- Neuroscience
Human fetal development has been associated with brain health at later stages. It is unknown whether growth in utero, as indexed by birth weight (BW), relates consistently to lifespan brain characteristics and changes, and to what extent these influences are of a genetic or environmental nature. Here we show remarkably stable and lifelong positive associations between BW and cortical surface area and volume across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4–82 y of age, w/386 monozygotic twins, followed for up to 8.3 y w/12,088 brain MRIs). In contrast, no consistent effect of BW on brain changes was observed. Partly environmental effects were indicated by analysis of twin BW discordance. In conclusion, the influence of prenatal growth on cortical topography is stable and reliable through the lifespan. This early-life factor appears to influence the brain by association of brain reserve, rather than brain maintenance. Thus, fetal influences appear omnipresent in the spacetime of the human brain throughout the human lifespan. Optimizing fetal growth may increase brain reserve for life, also in aging.
