Abstract
The common marmoset (Callithrix jacchus) is a non-human primate that could prove useful as human pharmacokinetic and biomedical research models. The cytochromes P450 (P450s) are a superfamily of enzymes that have critical roles in drug metabolism and disposition via monooxygenation of a broad range of xenobiotics; however, information on some marmoset P450s is currently limited. Therefore, identification and quantitative analysis of tissue-specific mRNA transcripts, including those of P450s and flavin-containing monooxygenases (FMO, another monooxygenase family), need to be carried out in detail before the marmoset can be used as an animal model in drug development. De novo assembly and expression analysis of marmoset transcripts were conducted with pooled liver, intestine, kidney, and brain samples from three male and three female marmosets. After unique sequences were automatically aligned by assembling software, the mean contig length was 718 bp (with a standard deviation of 457 bp) among a total of 47,883 transcripts. Approximately 30% of the total transcripts were matched to known marmoset sequences. Gene expression in 18 marmoset P450- and 4 FMO-like genes displayed some tissue-specific patterns. Of these, the three most highly expressed in marmoset liver were P450 2D-, 2E-, and 3A-like genes. In extrahepatic tissues, including brain, gene expressions of these monooxygenases were lower than those in liver, although P450 3A4 (previously P450 3A21) in intestine and P450 4A11- and FMO1-like genes in kidney were relatively highly expressed. By means of massive parallel long-read sequencing and short-read technology applied to marmoset liver, intestine, kidney, and brain, the combined next-generation sequencing analyses reported here were able to identify novel marmoset drug-metabolizing P450 transcripts that have until now been little reported. These results provide a foundation for mechanistic studies and pave the way for the use of marmosets as model animals for drug development in the future.
Highlights
The common marmoset (Callithrix jacchus) is a non-endangered member of the New World non-human primate family Callitrichidae native to northern and eastern Brazil [1,2,3,4,5]
One of the advantages of the common marmoset as an animal model for biomedical research is that its cells exhibit cross-reactivity with human cytokines and hormones [4]
For cDNA sequencing, eight total RNA samples were pooled in equal quantities, and the preparation of a normalized cDNA library for Roche GS FLX+ sequencing was carried out as follows: poly(A)+ RNA was isolated from the above RNA pool, and firststrand cDNA synthesis was primed with a N6 randomized primer
Summary
The common marmoset (Callithrix jacchus) is a non-endangered member of the New World non-human primate family Callitrichidae native to northern and eastern Brazil [1,2,3,4,5] It has attracted considerable attention as a potentially useful animal model in fields such as neuroscience, stem cell research, drug toxicology, immunity and autoimmune diseases, reproductive biology, and regenerative medicine [2] because of its size, availability, and unique biological characteristics [1]. RNAseq has several advantages over other expression profiling technologies, including higher sensitivity and the ability to detect splicing isoforms and somatic mutations [13] Because it is not restricted by the absence of an available reference genome sequence, this approach has been applied in decoding the genomes of several non-model organisms, providing valuable information on gene function, cell responses, and evolution [14,15,16]. The results of this study will be an important resource for future biomedical research and will facilitate the use of the common marmoset as an animal model in new drug development
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