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Researchers Map Blood Cell Progenitor Cell Line Transcriptome

NEW YORK (GenomeWeb News) – Using new and existing gene expression and other transcript data, an American research team has mapped the transcriptome of human stem-progenitor cells destined to become cells in the blood system. The work is scheduled to appear online this week in the Proceedings of the National Academy of Sciences.

Researchers from Northwestern University, Cold Spring Harbor Laboratory, and the University of Chicago evaluated nearly half a million transcripts from a hematopoietic stem-progenitor cell line called CD34+. Along with expression patterns, the team gauged alternative initiation, splicing, and adenylation patterns in the cells, developing a CD34+ transcriptome map that may offer insights into the process of hematopoiesis.

"Our study provides a current view on gene expression in human CD34+ cells and reveals that early hematopoiesis is an orchestrated process with the involvement of over half of the human genes distributed in various functions," senior author San Ming Wang, a hematology and oncology researcher at the Evanston Northwestern Healthcare Research Institute, and colleagues wrote. "The data generated from our study provide a comprehensive and uniform resource for studying hematopoiesis and stem cell biology."

Several previous studies have attempted to characterize the genetics underlying hematopoiesis, the transition from hematopoietic stem cells to progenitor cells to mature blood system cells. But, the authors noted, researchers' understanding of gene expression in blood progenitor cells is incomplete.

For the latest study, Wang and his team integrated serial analysis of gene expression, or SAGE, with existing messenger RNA sequence information from databases and published reports to characterize the transcriptome of human CD34+ hematopoietic stem-progenitor cells from the bone marrow of three healthy donors.

The researchers found 459,482 transcript signatures in the CD34+ cell line, representing about 56 percent of the human genes in the RefSeq messenger RNA and SAGEmap databases.

Among them were 59 genes involved in various aspects of stem cell self-renewal, 574 transcription factor genes in nearly 200 families, genes involved in ten different signal transduction pathways, almost 100 kinase genes, and dozens of microRNA sequences. The researchers also detected high expression of several miRNA precursors, which they speculated are important for regulating early hematopoiesis function.

When they characterized the frequency and nature of alternative transcripts — derived from alternative transcription initiation, post-transcriptional processes such as alternative splicing or adenylation patterns, or antisense and non-protein coding transcription — the researchers found 157 genes with one promoter and nearly 350 genes with multiple promoters in the CD34+ cell line.

In general, promoters used by genes with multiple promoters had atypical structures, leading the authors to conclude that "alternative transcriptional initiation is commonly used by the genes expressed in CD34+ cells." The CD34+ cells also revealed evidence of antisense transcription: about a quarter of the annotated antisense sequence tags and almost 40 percent of known non-coding transcripts turned up in the cell line.

In an effort to find gene expression signatures that could distinguish between CD34+ cells, their embryonic cell precursors, and mature hematopoietic cells, the researchers used SAGE tags to identify 220 genes that were either more highly expressed in CD34+ cells or only expressed in these cells.

Finally, the team pulled the CD34+ transcriptome information together into a genome-wide map — containing information on exons and introns, antisense sequences, promoter information, and more. The map has been integrated with the University of California at Santa Cruz human genome browser and is freely available online.

Although the transcriptome data sheds new light on the nature of CD34+ cells, it likely doesn't represent the complete transcriptome for this line, the authors noted. Down the road, they added, it will be necessary to not only determine how complete the current data set is, but also come up with markers to distinguish between CD34+ cells at different stages of maturity.

"Data from the study show that early hematopoiesis is an orchestrated process involving over half of the human genes and indicate that systems approaches will be required to fully reveal the genetic base of hematopoiesis," the authors wrote.

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