Transcriptome analysis reveals high tumor heterogeneity with respect to re-activation of stemness and proliferation programs

Significant alterations in signaling pathways and transcriptional regulatory programs together represent major hallmarks of many cancers. These, among all, include the reactivation of stemness, which is registered by the expression of pathways that are active in the embryonic stem cells (ESCs). Here, we assembled gene sets that reflect the stemness and proliferation signatures and used them to analyze a large panel of RNA-seq data from The Cancer Genome Atlas (TCGA) Consortium in order to specifically assess the expression of stemness-related and proliferation-related genes across a collection of different tumor types. We introduced a metric that captures the collective similarity of the expression profile of a tumor to that of ESCs, which showed that stemness and proliferation signatures vary greatly between different tumor types. We also observed a high degree of intertumoral heterogeneity in the expression of stemness- and proliferation-related genes, which was associated with increased hazard ratios in a fraction of tumors and mirrored by high intratumoral heterogeneity and a remarkable stemness capacity in metastatic lesions across cancer cells in single cell RNA-seq datasets. Taken together, these results indicate that the expression of stemness signatures is highly heterogeneous and cannot be used as a universal determinant of cancer. This calls into question the universal validity of diagnostic tests that are based on stem cell markers

Efficient Parameterized Algorithm for Biopolymer Structure-Sequence Alignment

Abstract. Computational alignment of a biopolymer sequence (e.g., an RNA or a protein) to a structure is an effective approach to predict and search for the structure of new sequences. To identify the structure of remote homologs, the structure-sequence alignment has to consider not only sequence similarity but also spatially conserved conformations caused by residue interactions, and consequently is computationally intractable. It is difficult to cope with the inefficiency without compromising alignment accuracy, especially for structure search in genomes or large databases. This paper introduces a novel method and a parameterized algorithm for structuresequence alignment. Both the structure and the sequence are represented as graphs, where in general the graph for a biopolymer structure has a naturally small tree width. The algorithm constructs an optimal alignment by finding in the sequence graph the maximum valued subgraph isomorphic to the structure graph. It has the computational time complexity O(k t N 2) for the structure of N residues and its tree decomposition of width t. The parameter k, small in nature, is determined by a statistical cutoff for the correspondence between the structure and the sequence. The paper demonstrates a successful application of the algorithm to developing a fast program for RNA structural homology search.

Time and space efficient RNA-RNA interaction prediction via sparse folding

In the past few years, a large set of new regulatory ncRNAs have been identified, but the number of experimentally verified targets is considerably low. Thus, computational target prediction methods are on high demand. Whereas all previous approaches for predicting a general joint structure have a complexity of O(n 6) running time and O(n 4) space, a more time and space efficient interaction prediction that is able to handle complex joint structures is necessary for genome-wide target prediction problems. In this paper we show how to reduce both the time and space complexity of RNA-RNA interaction prediction problem as described by Alkan et al. [1] by a linear factor via dynamic programming sparsification- which allows to safely discard large portions of DP tables. Applying sparsification techniques reduces the complexity of the original algorithm to O(n 4 ψ(n)) in time and O(n 2 ψ(n) + n 3) in space for some function ψ(n), which turns out to have small values for the range of n that we encounter in practice. By the use of polymer-zeta property for RNA-structures, we demonstrate that ψ(n) = O(n) on average. We evaluate our sparsified algorithm for RNA-RNA interaction prediction through total free energy minimization, based on the energy model of Chitsaz et al. [11], on a set of known interactions. Our results confirm the significant reduction of time and space requirements in practice

biRNA: Fast RNA-RNA Binding Sites Prediction

Abstract. We present biRNA, a novel algorithm for prediction of binding sites between two RNAs based on minimization of binding free energy. Similar to RNAup approach [29], we assume the binding free energy is the sum of accessibility and the interaction free energies. Our algorithm maintains tractability and speed and also has two important advantages over previous similar approaches: 1) it is able to predict multiple simultaneous binding sites and 2) it computes a more accurate interaction free energy by considering both intramolecular and intermolecular base pairing. Moreover, biRNA can handle crossing interactions as well as hairpins interacting in a zigzag fashion. To deal with simultaneous accessibility of binding sites, our algorithm models their joint probability of being unpaired. Since computing the exact joint probability distribution is intractable, we approximate the joint probability by a polynomially representable graphical model namely a Chow-Liu tree-structured Markov Random Field. Experimental results show that biRNA outperforms RNAup and also support the accuracy of our approach. Our proposed Bayesian approximation of the Boltzmann joint probability distribution provides a powerful, novel framework that can also be utilized in other applications.