Huelsken J: Cell-type-specific transcriptomics in chimeric models using transcriptome-based masks

Regulatory networks involving different cell types control inflammation, morphogenesis and tissue homeostasis. Cell-type-specific transcriptional pro-filing offers a powerful tool for analyzing such cross-talk but is often hampered by mingling of cells within a tissue. Here, we present a novel method that performs cell-type-specific expression measure-ments without prior cell separation. This involves inter-species transplantation or chimeric co-culture models among which the human mouse system is frequently used. Here, we exploit the sufficiently divergent transcriptomes of human and mouse in conjunction with high-density oligonucleotide arrays. This required a masking procedure based on transcriptome databases and exhaustive fuzzy mapping of oligonucleotide probes onto these data. The approach was tested in a human–mouse experiment, demonstrating that we can efficiently measure species-specific transcriptional profiles in chimeric RNA samples without physically sep-arating cells. Our results stress the importance of transcriptome databases with accurate 30 mRNA termination for computational prediction of accurate probe masks. We find that most human and mouse 30-untranslated region contain unique stretches to allow for an effective control of cross-hybridization between the two species. This approach can be applied to xenograft models studying tumor– host interactions, morphogenesis or immune responses