80 research outputs found
Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline
The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline
DNA methylation dynamics of the human preimplantation embryo
In mammals, cytosine methylation is predominantly restricted to CpG dinucleotides and stably distributed across the genome, with local, cell type-specific regulation directed by DNA binding factors1-3. This comparatively static landscape dramatically contrasts the events of fertilization, where the paternal genome is globally reprogrammed. Paternal genome demethylation includes the majority of CpGs, though methylation is maintained at several notable features4-7. While these dynamics have been extensively characterized in the mouse, only limited observations are available in other mammals, and direct measurements are required to understand the extent to which early embryonic landscapes are conserved8-10. We present genome-scale DNA methylation maps of human preimplantation development and embryonic stem cell (ESC) derivation, confirming a transient state of global hypomethylation that includes most CpGs, while sites of persistent maintenance are primarily restricted to gene bodies. While most features share similar dynamics to mouse, maternally contributed methylation is divergently targeted to species-specific sets of CpG island (CGI) promoters that extend beyond known Imprint Control Regions (ICRs). Retrotransposon regulation is also highly diverse and transitions from maternally to embryonically expressed, species-specific elements. Together, our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation
The impact of transposable element activity on therapeutically relevant human stem cells
Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative
medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing
worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a
wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use,
including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and
molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic
potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell
genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human
stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and
pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We
describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome,
and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only
represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell
genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the
most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the
assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for
the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016-
21395 and SAF2015â71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015â71589-
P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the
Federal Republic of Germany (FKZ2518FSB403)
Recent developments in genetics and medically assisted reproduction : from research to clinical applications
Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.Peer reviewe
The Microprocessor controls the activity of mammalian retrotransposons
More than half of the human genome is made of transposable elements whose ongoing mobilization is a driving force in genetic diversity; however, little is known about how the host regulates their activity. Here, we show that the Microprocessor (Drosha-DGCR8), which is required for microRNA biogenesis, also recognizes and binds RNAs derived from human long interspersed element 1 (LINE-1), Alu and SVA retrotransposons. Expression analyses demonstrate that cells lacking a functional Microprocessor accumulate LINE-1 mRNA and encoded proteins. Furthermore, we show that structured regions of the LINE-1 mRNA can be cleaved in vitro by Drosha. Additionally, we used a cell cultureâbased assay to show that the Microprocessor negatively regulates LINE-1 and Alu retrotransposition in vivo. Altogether, these data reveal a new role for the Microprocessor as a post-transcriptional repressor of mammalian retrotransposons and a defender of human genome integrity.S.R.H. was supported by a Marie Curie Intra-European Fellowship and a Marie Curie CIG-Grant (PCIG10-GA-2011-303812). M.P. and E.E. were supported by the Spanish Ministry of Science (BIO2011-23920) and by the Sandra Ibarra Foundation (CSD2009-00080). M.P. is supported by the Novo Nordisk Foundation. J.L.G.-P. is supported by FP7-PEOPLE-2007-4-3-IRG, CICE-FEDER-P09-CTS-4980, PeS-FEDER-PI-002, FIS-FEDER-PI11/01489 and the Howard Hughes Medical Institute (IECS-55007420). J.F.C. was supported by Core funding from the Medical Research Council and by the Wellcome Trust (grant 095518/B/11/Z)
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