Reconstruction of Gene Regulatory Networks from RNA-Seq Data Jianlin Jack Cheng Computer Science Department University of Missouri, Columbia ACM-BCB, 2014

Big Data Challenge in Genomic Era DNA/RNA Sequencing Mass Spectrometry Biological Experiments Biological Experiments Genomics Transcriptomics Proteomics Metabolomics … Genomics Transcriptomics Proteomics Metabolomics … Biological System Analysis Knowledge Omics Data

Expression Profiles of Genes under Multiple Conditions / Time Points Con 1Con 2Con 3Con 4Con 5Con 6Con 7Con 8…. Gene … Gene 2 Gene 3 Gene 4 ….

Gene Regulatory Networks (GRN) Bar-Joseph et al., 2003 GRN of yeast in rich medium Transcription factor (TF) regulates a gene TF1 TF2 TF3 Gene regulatory module

Bayesian Probabilistic Modeling Assign genes into co-regulated modules Construct regulatory relations of each module PosteriorLikelihood Prior

Gene Regulatory Network Modeling Zhu et al., 2013 Join

Gene Regulatory Logic of a Gene Module as a Decision Tree One Gene Module gene 1 gene 2 gene 3 …. gene n Biological Conditions (Treatments) in Columns Transcription factors and binary regulatory tree Low Expression High Expression

Regulatory Tree Construction Zhu et al., 2013 g1g2.gi..gng1g2.gi..gn μ 1, σ 1 μ 2, σ 2 Gaussian Mixture Pick a TF Divide conditions into two subsets based expression states Calculate probability

Regulatory Tree Construction Zhu et al., 2013 g1g2.gi..gng1g2.gi..gn Gaussian Mixture Repeat at next level

Regulatory Tree Construction Pick a TF Divide conditions based on TF states Calculate likelihood Select TF maximizing likelihood Repeat Zhu et al., 2013 g1 g2. gi. gn Gaussian Mixture Algorithm

Gene Re-Assignment μ1σ1μ1σ1 μ2σ2μ2σ gigi Regulatory Tree of a Module

RNA-Seq Data of Soybean Nodulation An important source of protein and oil Nitrogen fixation enabled by soybean-rhizobia symbiotic interactions Nodule

Gene Regulatory Modules of Differentially Expressed Genes A TF functioning in nodulation according to literature. NSP, whose homologous protein is a nodulation signaling in rice. One out of 10 modules Zhu et al., 2013

Application to Other Species Arabidopsis Drosophila Mouse Human … Soybean proteins affect TWIST2 – a novel protein related to Kidney disease? Helix-loop-helix transcription factor 2

Acknowledgements Students Deb Bhattacharya Renzhi Cao Jie Hou Jilong Li Matt Spencer Trieu Tuan Mingzhu Zhu Collaborators Jim Birchler, Bill Folk, Kevin Fritsche, Michael Greenlief, Zezong Gu, Mark Hannink, Trupti Joshi, Dennis Lubahn, Valeri Mossine, Alan Parrish, Frank Schmidt, Gary Stacey, Grace Sun, John Walker, Dong Xu

Binding Site Analysis MEME + TomTom to identify two binding sites: BetabetaAlphazinc, finger and Leucine Zipper TFs in GRAS family contain proteins binding to the motifs.

Function Enrichment Validation Function predicted by MULTICOM-PDCN P-value calculated by hypergeometric distribution. Some functions are related to formation of nodule organ. Zhu et al., 2013

I: TF-TF interactions by STRING, L: Literature Function Support Protein Interaction and Literature Validation Zhu et al., 2013

Computational Model Evaluation

GRN of Human Prostate Cancer Under Botanical Treatments Lu et al., submitted

Li et al., submitted.