04:30pm Wednesday 22 November 2017

Repetitive elements shape embryonic chromatin landscape

Retrotransposons are repetitive elements that form almost half of the mammalian genome. Even though they are so common, they have previously been considered to be fairly insignificant. Together with colleagues from the USA, scientists from the Helmholtz Zentrum München have now shown in ‘Nature Genetics’ that retrotransposons play an important role in embryonic development.

Picture of a murine 2-cell stage embryo

A murine 2-cell stage embryo: L1 transcripts are visualized in white, DNA is shown in blue. Source: Helmholtz Zentrum München

The researchers specifically investigated the role of so-called LINE1 (L1) elements, the most abundant retrotransposon family in mammals.* “We already knew L1 elements to be highly expressed in early embryogenesis and so we wanted to know if this transcription is important in the events taking place in the early embryo” says Prof. Dr. Maria Elena Torres-Padilla who headed the study. She is director of the Institute of Epigenetics and Stem Cells (IES) at Helmholtz Zentrum München and professor of Stem Cell Biology at the Ludwig-Maximilians-Universität München (LMU).

“Critical for the development of the embryo”

Examining the expression of L1 in an experimental model, the researchers observed a peak when the embryo consists of only 2 cells, followed by a decrease in expression by the time the embryo attaches to womb of the mother. These stages are crucial for a successful pregnancy. To understand the importance of L1 elements they used artificially designed transcription factors (TALE, for transcription activator-like effector) to prevent or promote L1 expression in embryos. “We found that too much or too little L1 expression caused development to come to a halt” explains Dr. Joanna Jachowicz (IES), first author of the paper. “This means that the precise timing and level of retrotransposon expression is critical for the development of the embryo.”

Unexpectedly, the scientists showed that the mechanism behind this regulation was independent of the coding nature of the transcript and of retrotransposition, that is, the ability of these elements to ‘jump’ to other parts of the genome. The researchers instead turned their attention to the chromatin**. Using their engineering approach, the researchers showed that expressing L1 caused chromatin to be more open, while stopping L1 expression caused chromatin to be more tightly packed.

“These results identify a novel role for retrotransposons in shaping the chromatin ‘landscape’ necessary for the early developmental programme”, explains Torres-Padilla. “It was previously assumed that the activation of retrotransposons was simply a side-effect of the chromatin remodelling occurring after fertilisation, a process termed epigenetic reprogramming. Our study demonstrates that L1 elements have a specific role in regulating chromatin accessibility which in turn is necessary for the correct developmental programme to take place. This study is hugely significant in assigning a role to a large amount of the mammalian genome at the very earliest stages of life.”

In the future, the scientists would like to explore this process further and investigate whether other transposable elements have similar functions. “The overall aim of our research is to understand the processes occurring in the early embryo” adds Torres-Padilla. “This is a very fascinating stage of development because all the cell types of the body will arise from the single cell present after fertilisation”. This is particularly relevant for the field of regenerative medicine, which aims to create different cell types and organs in the petri-dish for therapeutic use.

Further Information

* 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.

** Chromatin is the genetic material (DNA) together with the proteins that package and organize it. After fertilization, chromatin is extensively reorganized which is particularly interesting because the density with which the chromatin is packaged determines if certain genes can be transcribed or not.

Background:
By identifying retrotransposon activation as one potential mechanism enabling chromatin openness, this work opens up avenues to manipulate chromatin accessibility in the context of cell reprogramming, the researchers say. Recently, stem cell researchers at Helmholtz Zentrum München showed that dynamic changes in a subtype of Histones (H1) expression and localization are linked with chromatin remodeling and might be critical for transitions in chromatin structure during reprogramming. These observations also provide new insights into the chromatin changes underlying epigenetic reprogramming and pave the way for a better understanding of the mechanisms behind totipotency and the establishment of specific epigenetic states.

Original Publication:
Jachowicz, J.W. et al. (2017): LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo, Nature Genetics, 2017, DOI: 10.1038/ng.3945

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München 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. 
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.

 

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. 

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