Abstract
PROM1 is the gene encoding prominin-1 or CD133, an important cell surface marker for the isolation of both normal and cancer stem cells. PROM1 transcripts initiate at a range of transcription start sites (TSS) associated with distinct tissue and cancer expression profiles. Using high resolution Cap Analysis of Gene Expression (CAGE) sequencing we characterize TSS utilization across a broad range of normal and developmental tissues. We identify a novel proximal promoter (P6) within CD133+ melanoma cell lines and stem cells. Additional exon array sampling finds P6 to be active in populations enriched for mesenchyme, neural stem cells and within CD133+ enriched Ewing sarcomas. The P6 promoter is enriched with respect to previously characterized PROM1 promoters for a HMGI/Y (HMGA1) family transcription factor binding site motif and exhibits different epigenetic modifications relative to the canonical promoter region of PROM1.
Highlights
Surface markers play an important role in the purification of stem and progenitor cells
CAGE samples across a broad range of cell and tissue types and a series of melanoma cell lines, it has been possible to reveal a strong association between a specific new promoter and clonogenic CD133+ cells
These findings provide evidence of multiple regulatory events contributing to the diversity of PROM1 expression and indicate a potential role for HMGI/Y in combination with epigenetic changes to initiate transcription from P6 in less differentiated cells or stem cells, resulting in an upregulation of CD133
Summary
Surface markers play an important role in the purification of stem and progenitor cells. CD133+ cells have been broadly identified in nonhematopoetic tissues during differentiation in vitro and in vivo (Bussolati et al, 2005; Lee et al, 2005; Snippert et al, 2009) and have been isolated from brain and other cancers that possess stem-cell properties. In colon cancers CD133+ and CD133− populations have been found to be capable of tumor initiation in xenografts (Shmelkov et al, 2008), and both cell fractions have substantial tumor initiating activity in melanoma, lung, and ovarian cancer (Meng et al, 2009; Shackleton, 2010; Stewart et al, 2011), making CD133 a controversial marker for cancer stem cells (LaBarge and Bissell, 2008). A functional role for CD133 in suppression of neuroblastoma differentiation has been described (Takenobu et al, 2010), further complicating the understanding of its role and value as a suitable surface marker
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