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Blueprint Team Describes Epigenetic, Transcriptional Patterns at Play During Blood Cell Development

NEW YORK (GenomeWeb) – A set of studies published online today in Science is starting to spell out the epigenetic processes that regulate transitions from stem cells into various blood cell types — from oxygen-carrying red blood cells to the diverse white blood cells behind the body's complex immune responses.

The research was done through Blueprint, a European consortium focused on the regulatory and transcriptional features that determine blood cell differentiation and development.

Members of the team have been using approaches such as DNaseI sequencing, bisulfite sequencing, and RNA sequencing to map histone modification and methylation profiles, gene expression, and transcript splicing patterns in a range of blood cell precursors found in blood and bone marrow samples, Hendrik Stunnenberg, a molecular biology researcher at Radboud University and Blueprint coordinator, told GenomeWeb Daily News.

"Blueprint is totally focused on blood and totally on primary material. We're looking at primary cells sorted out from blood or bone marrow and analyzing the state of their epigenome, transcriptome, DNA methylation profiles, and so on," Stunnenberg explained, noting that Blueprint itself is part of a larger International Human Epigenome Consortium.

Stunnenberg was senior author on one of the new papers, which described transcriptomic and epigenomic profiles associated with the differentiation from monocytes to macrophage white blood cells.

For that study, he and his colleagues assessed monocytes as well as more differentiated macrophage cells in naïve, "tolerized" (sepsis-like), or "trained" states.

Although the innate branch of the immune system is not typically thought of as having a "memory," Stunnenberg said, members of the team had previously found clues that macrophages could achieve the latter, trained state during the monocyte-to-macrophage differentiation step, leading to acquired resistance to subsequent immune challenges.

Results from the new analysis suggest that process hinges on epigenetic regulators that prompt some pathways to become active and others to decline in activity as macrophages develop trained immunity.

A related study in Science offered additional details about the metabolic pathways involved in macrophage training. In that study, the team used histone modification and transcriptome patterns to detect shifts in cells' reliance on glycolysis and oxidative phosphorylation as monocytes from the blood — which were exposed to an oxygen- and nutrient-rich environment — adopted roles as macrophages residing in solid tissues.

"They change their whole metabolic pathway," Stunnenberg said. "And if you block that transition … you block the training aspect [of macrophage development]."

For a third Science study, meanwhile, Blueprint investigators used deep RNA sequencing to decipher transcriptional patterns in eight different types of hematopoietic progenitor cells, uncovering thousands of transcripts specific to a given blood cell type.

They also tracked transcript splicing events behind blood cell development, identifying almost 8,000 previously undescribed splice junction sites in the process.

Across the blood precursor cells considered, for instance, the team saw some 2,300 alternative splicing sites that are used differently depending on the specific blood cell precursor considered — a set that often involved transcripts coinciding with known regulatory genes.

So far, the Blueprint team has generated data for around 40 or 50 different cell types, Stunnenberg said, and is continuing to systematically characterize blood cells from every branch of their differentiation and development in samples from healthy donors.

Once they have established a complete framework of the regulatory and transcriptional events used to produce blood and immune system components, Blueprint members hope to secure sufficient funding to systematically assess various disease states — from type 2 diabetes, rheumatoid arthritis, or inflammatory bowel disease to blood cancers and response to related treatments — in comparison with these references.

"Cord blood stem cells are used to provide curative treatments for patients with blood cell cancers," Lu Chen, a researcher affiliated with the Wellcome Trust Sanger Institute, the University of Cambridge, and the National Health Service, said in a statement. "After transplantation some donated stem cell preparation[s] fail to regenerate certain cell types in the correct amounts."

"To tackle these problems, we need to understand blood cell development at the level of the transcripts and splice junctions that influence the fate of a hematopoietic stem cell," added Chen, who was first author on the blood progenitor transcriptome study. "This catalogue provides the level of detail that we’ve been missing."