Drawing a BLUEPRINT for blood cells

26 September 2014

Even as the human genome was being deciphered, it was apparent that knowing the sequence and how DNA is organised in chromosomes isn’t enough to understand how it is used.

There are around 200 different types of cells in the body and every type has the same DNA content, yet cells differ greatly in their appearance and function. It’s clear that the same genetic information must be interpreted differently in different cells – another layer of detail is needed to understand how cells receive and respond to instructions in their DNA.

Different types of cells change in response to signals from the outside and as a consequence of aging. These changes need to be understood, especially as their altered states underlie diseases. Epigenetics aims to unravel the structural modification of chromosomes that determines how regions of the DNA are packaged and its use in a certain type of cell. The newly gained layers of information about regulation are placed on top of what we already know about the genome to form a master plan or blueprint of the cell.

BLUEPRINT is a European Commission-funded project that aims to gather these layers of information to develop our understanding of blood disorders. The project has just published its first suite of papers, uncovering differences between two important types of white blood cell, identifying changes in the metabolism of some immune cells and cataloguing stages in the development of blood cells from stem cells.

Paper 1: Epigenetic programming of immune system training unravelled

In the first of these studies, researchers uncovered epigenetic programs that distinguish two different types of white blood cell.

During infection, monocytes, a special type of white blood cell, infiltrate infected tissue where they differentiate into macrophages, which are white blood cells that engulf and digest invading pathogens. Both monocytes and macrophages belong to the body’s first line of defence, its innate immune system.

In individuals with an infection, activation of monocytes and differentiation of macrophages can differ depending of the type of pathogen or infection. During severe infections and sepsis, monocytes and macrophages undergo a period of reduced activity 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 for viruses such as measles, the monocytes and macrophages react more strongly to pathogens, in a process called trained immunity.

This study demonstrates that distinct epigenetic programs execute immune tolerance and trained immunity, and describes novel specific pathways that induce these processes.

Paper 2: Trained immunity in white blood cells is induced by monocyte glycolysis

A second study also 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 pathway using glucose (oxidative phosphorylation) towards glycolysis, which is a rapid shortcut for increasing energy production for the cell. This switch enables monocytes and macrophages to ensure the energy necessary for an increased activity.

Paper 3: Catalogue of how blood cells are formed from blood stem cells

In the third study published by BLUEPRINT, researchers report on the processes leading to the formation of different types of blood cell. For the first time, they provide a comprehensive catalogue of transcription factors and other proteins that regulate this sophisticated process.

To manufacture a protein, cells need to transcribe the DNA in the nucleus into messengers called RNA. The spectrum of RNA molecules carries the instructions for how cells produce proteins. BLUEPRINT researchers discovered the extent by which the RNA is cut and pasted together in different ways during the various events determining cell fate and development, leading to specific constellations of proteins for each of these stages.

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.

References

• Paper 1: Saeed S, et al. (2014) Epigenetic programming during monocyte to macrophage differentiation and trained innate immunity. Science. DOI:10.1128/JVI.01333-14
• Paper 2: Cheng S, Quintin J, et al. (2014) Epigenetic profiling identifies mTOR/HIF1α-dependent induction of glycolysis as the cellular metabolic basis of trained immunity; Monocyte glycolysis induces trained immunity. Science. DOI: 10.1126/science.1250684
• Paper 3: Chen L, et al. (2014) Transcriptional diversity during lineage commitment of human blood progenitors. Science. DOI: 10.1126/science.1251033

Related Links:

• BLUEPRINT - A BLUEPRINT of Haematopoietic Epigenomes
• The University of Cambridge
• Radboud University
• Wellcome Trust Sanger Institute