Conversion of random X-inactivation to imprinted X-inactivation by maternal PRC2
Abstract
Imprinted X-inactivation silences genes exclusively on the paternally-inherited X-chromosome and is a paradigm of transgenerational epigenetic inheritance in mammals. Here, we test the role of maternal vs. zygotic Polycomb repressive complex 2 (PRC2) protein EED in orchestrating imprinted X-inactivation in mouse embryos. In maternal-null (Eedm-/-) but not zygotic-null (Eed-/-) early embryos, the maternal X-chromosome ectopically induced Xist and underwent inactivation. Eedm-/- females subsequently stochastically silenced Xist from one of the two X-chromosomes and displayed random X-inactivation. This effect was exacerbated in embryos lacking both maternal and zygotic EED (Eedmz-/-), suggesting that zygotic EED can also contribute to the onset of imprinted X-inactivation. Xist expression dynamics in Eedm-/- embryos resemble that of early human embryos, which lack oocyte-derived maternal PRC2 and only undergo random X-inactivation. Thus, expression of PRC2 in the oocyte and transmission of the gene products to the embryo may dictate the occurrence of imprinted X-inactivation in mammals.
Data availability
Sequencing data have been deposited in GEO under accession number GSE123173. The analyzed sequencing data are also included as Supplementary File 3.
-
Conversion of Random X-inactivation to Imprinted X-inactivation by Maternal PRC2NCBI Gene Expression Omnibus, GSE123173.
-
The transcriptome of a human polar body accurately reflects its sibling oocyteNCBI BioProject, PRJNA146903.
-
Gene expression during the first three days of human developmentNCBI BioProject, PRJEB8994.
-
Embryonic stem cell potency fluctuates with endogenous retrovirus activity.NCBI BioProject, PRJNA154207.
Article and author information
Author details
Funding
NIH Office of the Director (DP2-OD-008646)
- Sundeep Kalantry
National Institutes of Health (R01GM124571)
- Sundeep Kalantry
National Institutes of Health (R01HD095463)
- Sundeep Kalantry
National Institute of General Medical Sciences (T32GM07544)
- Marissa Cloutier
- Megan Trotter
March of Dimes Foundation (5-FY12-119)
- Sundeep Kalantry
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kavitha Sarma, Wistar Institute, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to protocols approved by the University Committee on Use and Care of Animals (UCUCA) at the University of Michigan (protocol #s PRO6455 and PRO8425).
Version history
- Received: December 10, 2018
- Accepted: April 1, 2019
- Accepted Manuscript published: April 2, 2019 (version 1)
- Version of Record published: May 29, 2019 (version 2)
Copyright
© 2019, Harris 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
-
- 4,478
- Page views
-
- 546
- Downloads
-
- 28
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
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)
Further reading
-
- Chromosomes and Gene Expression
- Genetics and Genomics
Endothelial cell subpopulations are characterized by unique gene expression profiles, epigenetic landscapes and functional properties.
-
- Cell Biology
- Chromosomes and Gene Expression
Histone H1 participates in chromatin condensation and regulates nuclear processes. Human somatic cells may contain up to seven histone H1 variants, although their functional heterogeneity is not fully understood. Here, we have profiled the differential nuclear distribution of the somatic H1 repertoire in human cells through imaging techniques including super-resolution microscopy. H1 variants exhibit characteristic distribution patterns in both interphase and mitosis. H1.2, H1.3, and H1.5 are universally enriched at the nuclear periphery in all cell lines analyzed and co-localize with compacted DNA. H1.0 shows a less pronounced peripheral localization, with apparent variability among different cell lines. On the other hand, H1.4 and H1X are distributed throughout the nucleus, being H1X universally enriched in high-GC regions and abundant in the nucleoli. Interestingly, H1.4 and H1.0 show a more peripheral distribution in cell lines lacking H1.3 and H1.5. The differential distribution patterns of H1 suggest specific functionalities in organizing lamina-associated domains or nucleolar activity, which is further supported by a distinct response of H1X or phosphorylated H1.4 to the inhibition of ribosomal DNA transcription. Moreover, H1 variants depletion affects chromatin structure in a variant-specific manner. Concretely, H1.2 knock-down, either alone or combined, triggers a global chromatin decompaction. Overall, imaging has allowed us to distinguish H1 variants distribution beyond the segregation in two groups denoted by previous ChIP-Seq determinations. Our results support H1 variants heterogeneity and suggest that variant-specific functionality can be shared between different cell types.