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How the embryo attaches
Retrotransposons* are commonly found in almost half the mammalian genome. However, though evenly distributed throughout the body, they had not been considered significant. Now, US scientists along with colleagues from the German Center for Environmental Health, Helmholtz Zentrum München, find retrotransposons actually play a significant role in embryo attachment.
The work is published in Nature Genetics.
"We already knew L1 elements to be highly expressed in early embryogenesis" explains Maria Elena Torres-Padilla PhD, who headed the study. By artificially preventing L1 expression in early embryogenisis, the scientists were able to identify that peak expression of L1 retrotrasposons occurs in the 2 cell embryo, and drops significantly after the embryo attaches to the uterine wall.
"Too much or too little L1 expression caused development to come to a halt. This means the precise timing and level of retrotransposon expression is critical to development of the embryo."
Unexpectedly, researchers found the mechanism behind regulation of L1 expression was independent of retrotransposition, that is, the ability of transposons to 'jump' to other parts of the genome. So they turned their attention to the chromatin - the DNA material and proteins that packages transposons.
After fertilization, chromatin is extensively reorganized and the density of the chromatin package determines if certain genes are accessible to being transcribed. Following this engineering approach, researchers showed that expressing L1 causes chromatin to be more open to transcription, while stopping L1 expression caused chromatin to be more tightly packed and inaccessible.
"These results identify a novel role for retrotransposons reshaping the chromatin as needed in early development. It was previously assumed activation of retrotransposons was simply a side-effect of chromatin remodelling following fertilization, also called 'epigenetic reprogramming.'
Torres-Padilla's group wants to continue exploring these processes in order to investigate whether other transposable elements have similar functions. "The overall aim of our research is to understand the processes occurring in the early embryo" she adds. "This is a fascinating stage of development as all cell types in the body arise from the single cell present after fertilization."
This period of transformation is also of particular interest to regenerative medicine in its desire to create different cell types and organs in the lab for therapeutic treatments.
* The term "retrotransposons" refers to a class of transposable DNA sequences that is structurally very similar to the retroviruses. Like their relatives, these elements are able to jump to other parts of the genome. The acronym LINE stands for long interspersed nuclear elements. L1 elements account for approximately 17 percent of the genetic material in humans and up to 40 percent in other mammals.
After fertilization, to initiate development, gametes are reprogramed to become totipotent. Approximately half of the mammalian genome consists of repetitive elements, including retrotransposons, some of which are transcribed after fertilization. Retrotransposon activation is generally assumed to be a side effect of the extensive chromatin remodeling underlying the epigenetic reprogramming of gametes. Here, we used a targeted epigenomic approach to address whether specific retrotransposon families play a direct role in chromatin organization and developmental progression. We demonstrate that premature silencing of LINE-1 elements decreases chromatin accessibility, whereas prolonged activation prevents the gradual chromatin compaction that occurs naturally in developmental progression. Preventing LINE-1 activation and interfering with its silencing decreases developmental rates independently of the coding nature of the LINE-1 transcript, thus suggesting that LINE-1 functions primarily at the chromatin level. Our data suggest that activation of LINE-1 regulates global chromatin accessibility at the beginning of development and indicate that retrotransposon activation is integral to the developmental program.
All authors: Joanna W Jachowicz, Xinyang Bing, Julien Pontabry, Ana Bokovic, Oliver J Rando, and Maria-Elena Torres-Padilla
The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de/en
The research of the Institute of Epigenetics and Stem Cells (IES) is focused on the characterization of early events in mammalian embryos. The scientists are especially interested in the totipotency of cells which is lost during development. Moreover, they want to elucidate who this loss is caused by changes in the nucleus. Their main goal is to understand the underlying molecular mechanisms which might lead to the development of new therapeutic approaches. http://www.helmholtz-muenchen.de/ies
As one of Europe's leading research universities, LMU Munich is committed to the highest international standards of excellence in research and teaching. Building on its 500-year-tradition of scholarship, LMU covers a broad spectrum of disciplines, ranging from the humanities and cultural studies through law, economics and social studies to medicine and the sciences. 15 percent of LMU's 50,000 students come from abroad, originating from 130 countries worldwide. The know-how and creativity of LMU's academics form the foundation of the University's outstanding research record. This is also reflected in LMU's designation of as a "university of excellence" in the context of the Excellence Initiative, a nationwide competition to promote top-level university research. http://www.en.lmu.de
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2-cell stage embryo: L1 retrotransposons are in white, DNA is shown in blue.
Image Credit: Helmholtz Zentrum München