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Molecular Biology

Gatekeepers of the genome

Transcription factors control gene activation in cells. By binding to specific segments of DNA, they enable the blueprints that code for cellular proteins to be produced. But how are such factors themselves regulated? Scientists at Helmholtz Zentrum München and Ludwig-Maximilians-Universität München have come closer to answering this question. Their work has been published in Nucleic Acid Research.

Gastrulation stage embryo showing gradients of transcription factor expression (Foxa2 in green and Sox17 in red). These gradients specify where lung, liver, pancreas and gastro-intestinal tract are formed along the anterior-posterior axis of the embryo ©Helmholtz Zentrum München

In the cell nucleus, the long DNA molecules that comprise the hereditary material are tightly folded into a highly condensed form. This makes it possible for the two meter of DNA found in every nucleus in the human body to be accommodated at all. Each double-stranded DNA is wrapped around millions of protein complexes composed of ‘histones’, and these ‘nucleosomes’ are in turn connected by linker histones. The resulting compactified fraction of the chromosomal DNA is referred to as ‘chromatin’.

However, in order to grow, differentiate and respond to changing conditions, every cell must be able to selectively activate the genes which provide the blueprints for synthesis of the proteins that it needs. This means that specific sets of genes within the tightly packaged chromatin must be made accessible to the enzymes responsible for ‘transcription’ of these blueprints. How do cells accomplish this task? How is the packaging of chromatin locally modified to enable transcription of precisely those segments of the DNA where these genes reside?

A specialized class of proteins, known as pioneer transcription factors (PTFs), is responsible for opening up the chromatin at particular sites. They do so by displacing nucleosomes from regions in which the DNA is tightly packed. PTFs thus serve as gatekeepers, which enable the transcriptional machinery to interact with the genes whose protein products are currently required. This of course raises the question of how PTFs actually clear the way and, perhaps even more important, how their actions are controlled. Heiko Lickert, director of the Institute of Diabetes- and Regeneration Research at Helmholtz Zentrum München, Gunnar Schotta at Biomedical Center of Ludwig-Maximilians-University Munich and team has now elucidated some aspects of this complex riddle.  

The researchers addressed these issues in laboratory experiments designed to uncover the mechanisms that enable embryonic stem cells to generate endodermal cells during mouse embryogenesis. These cells subsequently form inner organs of the body. It is known that a PTF named Foxa2 is involved in the process. Foxa2 interacts with specific binding sites in the DNA. This interaction can result in displacement of nucleosomes which makes DNA sequences that code for proteins essential for the development of endodermal tissues accessible for binding by other proteins. Indeed, Lickert and his colleagues have now shown that other TFs in addition to Foxa2 play an essential role in this process.

Furthermore, it appears as if Foxa2’s ability to recognize the binding sites that are important for the early development of endoderm is dependent on second layer of regulation. For gene regulation is mediated not only by binding of proteins to regulatory nucleotide sequences in the DNA. It can also involve the recognition of chemical tags attached to the nucleotide subunits of the DNA or to nucleosomal histones. “This latter type of control is referred to as ‘epigenetic’, because the modifications do not change the coding capacity of the DNA sequence itself. Thus attachment of epigenetic tags to histones also serves to modulate the accessibility of nucleosomal DNA”, says Lickert. Indeed, the researcher now showed that the density of epigenetic tags determines whether or not Foxa2 can bind and open up condensed chromatin. “These results reveal important details of the process by which a network of transcription factors can control the activity of key genes,” says Schotta.

Further Information

Original Publication:

Cernilogar, F.M. et al. (2019): Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2, Nucleic Acids Research, DOI: 10.1093/nar/gkz627

The research activities of the Institute of Diabetes and Regeneration Research (IDR) focus on the biological and physiological study of the pancreas and/or the insulin producing beta cells. Thus, the IDR contributes to the elucidation of the development of diabetes and the discovery of new risk genes of the disease. Experts from the fields of stem cell research and metabolic diseases work together on solutions for regenerative therapy approaches of diabetes. The IDR is part of the Helmholtz Diabetes Center (HDC).

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, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,500 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 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

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.