Expression Map of the Human Exome in CD34+ Cells and Blood Cells: Increased Alternative Splicing in Cell Motility and Immune Response Genes

Jean-François Schved,Samir Hamamah,Said Assou,Aurélie Cubizolle,Véronique Pantesco,John De Vos,Rima Benmahdi,Yoann Lannay,Tanguy Le Carrour,Céline Pangault,Sylvie Tondeur,Thierry Fest,Bernard Klein

doi:10.1371/journal.pone.0008990

Abstract

BackgroundHematopoietic cells are endowed with very specific biological functions, including cell motility and immune response. These specific functions are dramatically altered during hematopoietic cell differentiation, whereby undifferentiated hematopoietic stem and progenitor cells (HSPC) residing in bone marrow differentiate into platelets, red blood cells and immune cells that exit into the blood stream and eventually move into lymphoid organs or inflamed tissues. The contribution of alternative splicing (AS) to these functions has long been minimized due to incomplete knowledge on AS events in hematopoietic cells.Principal FindingsUsing Human Exon ST 1.0 microarrays, the entire exome expression profile of immature CD34+ HSPC and mature whole blood cells was mapped, compared to a collection of solid tissues and made freely available as an online exome expression atlas (Amazonia Exon! : http://amazonia.transcriptome.eu/exon.php). At a whole transcript level, HSPC strongly expressed EREG and the pluripotency marker DPPA4. Using a differential splicing index scheme (dsi), a list of 849 transcripts differentially expressed between hematopoietic cells and solid tissues was computed, that included NEDD9 and CD74. Some of these genes also underwent alternative splicing events during hematopoietic differentiation, such as INPP4B, PTPLA or COMMD6, with varied contribution of CD3+ T cells, CD19+ B cells, CD14+ or CD15+ myelomonocytic populations. Strikingly, these genes were significantly enriched for genes involved in cell motility, cell adhesion, response to wounding and immune processes.ConclusionThe relevance and the precision provided by this exon expression map highlights the contribution of alternative splicing to key feature of blood cells differentiation and function.

Highlights

The normal function of cells depends on the accurate expression of a large array of protein-coding messenger RNA
The relevance and the precision provided by this exon expression map highlights the contribution of alternative splicing to key feature of blood cells differentiation and function
No cell separation step was used prior to RNA extraction, these samples comprised the entire range of blood cells: polymorphonuclear leukocytes, lymphocytes, monocytes, platelets and red blood cells

Summary

Introduction

The normal function of cells depends on the accurate expression of a large array of protein-coding messenger RNA (mRNA). The functional importance of AS is even more highlighted by the finding that about 10% of genetic diseases caused by point mutation affect the spliceosome formation [2]. The importance of this level of gene regulation has been recognized in the hematopoietic system, especially immune cells, but this knowledge is still very limited [3,4]. Blood cells share numerous functional properties that distinguish them from other solid tissues, including cell motility and, for white blood cells, immune functions. The contribution of alternative splicing (AS) to these functions has long been minimized due to incomplete knowledge on AS events in hematopoietic cells

Methods

Results

Discussion

Conclusion