BLUEPRINT scientists spearheaded from Radboud and Cambridge Universities and the Welcome Trust Sanger Institute investigated epigenetics programs underlying decisions about cell fate in blood stem cells and during differentiation of monocytes to macrophages, two important types of white blood cells. They uncover epigenetic and metabolic programs that distinguish tolerant and trained macrophages1,2, furthering our understanding of how the immune system keeps infection at bay and providing invaluable resources to manipulate the immune system. BLUEPRINT scientists also highlight the complexity of the regulation of fating events that determine the states of closely related populations of blood progenitor cells3. Understanding the molecular basis of fate decisions is essential for the advancement of transplantation and regenerative medicine.
BLUEPRINT: Epigenetics of
After the human genome was deciphered, it became apparent that knowing the DNA code and how it is organised in chromosomes is insufficient to understand how the code is used to determine the identity of cells. There are lots of different types of cells in the body and each cell has the same DNA content, yet cells differ greatly in their appearance and function. They change in response to outside signals and as a consequence of aging and their altered states underlie diseases. Thus, the way the genetic information is used differs between each type of cell and this difference is in part determined by how DNA is packaged in chromosomes. Epigenetics aims at unravelling this packaging through structural adaptation of chromosomes which determines how DNA elements are regulated. The newly gained layers of information, which are unique to a particular type of cells are placed on "top of the genome" to form a master plan or blueprint of the cell.
BLUEPRINT is a High Impact Project receiving close to €30 million funding from the European Commission; 41 European universities and research institutes work with industry partners in what is one of the two first so-called European High Impact research initiatives. BLUEPRINT scientists aim at deciphering the epigenomes of more than 100 different types of blood cells.
"The BLUEPRINT achievements make a significant contribution to the International Human Epigenome Consortium (www.IHEC-epigenomes.org) that joins up epigenome data worldwide of hundreds of different types of cells in the body said Professor Hendrik Stunnenberg at the Radboud University Nijmegen in the Netherlands, who coordinates the BLUEPRINT endeavor.
A leap in the knowledge of
how the immune system keeps pathogens at bay
During an infectious period, monocytes from the blood infiltrate the infected tissue where they differentiate into macrophages to eliminate the invading pathogen. Both monocytes and macrophages are populations of cells belonging to the innate arm of the immune system. The innate immune cells act rapidly to eliminate invading pathogens, whilst lymphocytes, another type of white blood cells are more specific in their attack and therefor slower to act. BLUEPRINT researchers have identified differences in activity between monocytes and macrophages.
"The immune response of the host is much stronger regulated by environmental factors than we thought" remarked Mihai Netea who is Professor of Experimental Medicine at Radboud University Medical Center. He continued "We were surprised to see how different the blueprints of monocytes and macrophages were. It shows the strong effects of the different body compartments, setting up the monocytes to act quickly to an invading pathogen, whilst macrophages that reside in tissues like skin and gut are instructed to be more tolerant."
differentiation programmes for the monocytes
In individuals with infection, activation of monocytes and differentiation of macrophages can differ depending of the type of pathogen and infection. During severe infections and sepsis, monocytes and macrophages undergo a period of reduced activity or so called "tolerance". During this period the cells react much less efficiently to invading pathogens and the host is more prone to infections. In contrast, during other types of infections, and especially after vaccinations such as BCG or measles, the monocytes and macrophages react more strongly to pathogens, a process termed "trained immunity". This represents a de facto memory of innate immunity. One of the BLUEPRINT studies (ref.1) demonstrates that distinct epigenetic programs execute immune tolerance and trained immunity, and describes novel specific pathways that induce these processes. A 2nd study (ref.2) identified a novel dimension of innate immune memory, namely that cells undergoing trained immunity switch their internal metabolism: the process that insures the energy needed for a proper function. The BLUEPRINT researchers discovered that monocyte metabolism switches from, the normal way of using glucose by oxidative phosphorylation towards glycolysis - a rapid shortcut for increasing energy production for the cell. This switch enables monocytes and macrophages to insure the energy necessary for an increased activity in the fight against pathogens.
How are white cells formed
by the blood stem cell?
The 3rd study published by BLUEPRINT researchers reports on the processes leading to the formation of different types of blood cells, including the white ones by blood stem cells (ref.3). For the first time, a comprehensive catalogue of transcription factors and other proteins that regulate this sophisticated process has been generated. To manufacture a protein, cells need to transcribe the DNA in the nucleus into a messenger or so called RNA. The spectrum of RNA molecules carries the instruction for cells how to produce proteins. BLUEPRINT researchers discovered the extent by which the RNA is cut and pasted together in different ways during the various fating events, leading to specific constellations of proteins for each of these stages. "We have identified thousands of novel places where the RNA is processed in an alternative way" said Willem H Ouwehand, Professor of Experimental Haematology at the University of Cambridge and the Wellcome Trust Sanger Institute. The importance of the alternative splicing of RNA in blood cell development was illustrated using two different transcription factors. This effort confirmed the critical importance of the alternative processing of RNA molecules, which results in the formation of slightly altered forms of the same protein at different fating stages during the development of blood progenitor cells. "This new and freely available catalogue of RNA molecules in blood progenitor cells provides a rich resource for researchers worldwide", commented Dr Nicole Soranzo from the Wellcome Trust Sanger Institute in Cambridge. It will be of great value in studies which aim to manipulate blood stem cells and their progeny and is important for future developments in stem cell transplantation therapy, as well as efforts in regenerative medicine.
In the September 26th
issue of Science, 3 papers from the BLUEPRINT consortium are
1. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity
2. Transcriptional diversity during lineage commitment of human blood progenitors
3. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity
Also an 'In Depth' is dedicated to the 3 papers.
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