  High-throughput mRNA sequencing (RNA-Seq) is widely used for transcript
quantification of gene isoforms. Since RNA-Seq data alone is often not
sufficient to accurately identify the read origins from the isoforms for
quantification, we propose to explore protein domain-domain interactions as
prior knowledge for integrative analysis with RNA-seq data. We introduce a
Network-based method for RNA-Seq-based Transcript Quantification (Net-RSTQ) to
integrate protein domain-domain interaction network with short read alignments
for transcript abundance estimation. Based on our observation that the
abundances of the neighboring isoforms by domain-domain interactions in the
network are positively correlated, Net-RSTQ models the expression of the
neighboring transcripts as Dirichlet priors on the likelihood of the observed
read alignments against the transcripts in one gene. The transcript abundances
of all the genes are then jointly estimated with alternating optimization of
multiple EM problems. In simulation Net-RSTQ effectively improved isoform
transcript quantifications when isoform co-expressions correlate with their
interactions. qRT-PCR results on 25 multi-isoform genes in a stem cell line, an
ovarian cancer cell line, and a breast cancer cell line also showed that
Net-RSTQ estimated more consistent isoform proportions with RNA-Seq data. In
the experiments on the RNA-Seq data in The Cancer Genome Atlas (TCGA), the
transcript abundances estimated by Net-RSTQ are more informative for patient
sample classification of ovarian cancer, breast cancer and lung cancer. All
experimental results collectively support that Net-RSTQ is a promising approach
for isoform quantification.
