Press Release
Neurobiology
31.10.2016

Epigenetics and neural cell death

Cerebral cortex. Immunostained for Uhrf1 (neural stem cells, red). Picture: Vidya Ramesh

Researchers have demonstrated how deregulation of an epigenetic mechanism that is active only in the early phases of neurogenesis triggers the subsequent death of neural cells. The work was published by scientists based at Helmholtz Zentrum München and at LMU Munich in Genes and Development 

The generation of neurons from stem and progenitor cells is a complex, tightly regulated process known as neurogenesis. Researchers led by Prof. Dr. Magdalena Götz, Director of the Institute for Stem Cell Research at the Helmholtz Zentrum München and Chair of Physiological Genomics at LMU, have shown in collaboration with Professor Dr. Gunnar Schotta, Biomedical Center LMU, that epigenetic mechanisms which are brought into play at an early stage of neurogenesis, have an important impact on the subsequent fate of neurons.  

In order to elucidate the significance of early epigenetic modifications on the development of neural cells during embryogenesis in the mouse, Götz and her colleagues specifically inactivated the gene Uhrf1. This gene is known to control a number of epigenetic functions, including DNA methylation, and is active from very early stages of neurogenesis. The methylation of specific nucleotide bases in DNA often serves to switch genes off.  

Conditional knockout of Uhrf1, in a region of the forebrain, led to the activation of endogenous retroviral elements (ERV) in the genome, which are otherwise silenced by methylation. Further investigation revealed that members of the Tet family of enzymes are largely mediating the demethylation of the ERVs, thus appearing be functionally activated in the absence of Uhrf1. Moreover, these ERVs remained active not only in later stages of embryogenesis but also into postnatal stages, suggesting that their activation is non-reversible. The aberrant and ongoing activation of ERVs caused an accumulation of retroviral proteins in the affected cells and deregulation of genes and pathways. This in turn led to the progressive disruption of vital cellular processes and ultimately precipitated a massive wave of cell death.  

“Our results reveal that certain key factors – such as the gene Uhrf1 – that are transiently activated only in early neurogenesis can have a crucial impact on cell fate, which may only manifest weeks later,” says Götz. “Our model system provides us with fascinating insights into these mechanisms, which are also of great interest in the context of neurodegenerative diseases.”

Further information  

Publication: Ramesh, V. et al., Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration. Genes & Dev., doi: 10.1101/gad.284992.11 

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.  

The Institute of Stem Cell Research (ISF) investigates the basic molecular and cellular mechanisms of stem cell maintenance and differentiation. From that, the ISF then develops approaches in order to replace defect cell types, either by activating resting stem cells or by re-programming other existing cell types to repair themselves. The aim of these approaches is to stimulate the regrowth of damaged, pathologically changed or destroyed tissue.  

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.