Reconstruction of Gene Regulatory Networks from RNA-Seq Data

Jianlin Jack ChengComputer Science Department

University of Missouri, ColumbiaACM-BCB, 2014

Big Data Challenge in Genomic Era

DNA/RNA Sequencing

Mass Spectrometry

Biological Experiments

Biological Experiments

GenomicsTranscriptomics

ProteomicsMetabolomics

…

GenomicsTranscriptomics

ProteomicsMetabolomics

…

Biological System

AnalysisKnowledge

Omics Data

Expression Profiles of Genes under Multiple Conditions / Time

PointsCon 1 Con 2 Con 3 Con 4 Con 5 Con 6 Con 7 Con 8 ….

Gene 1 10 30 40 35 20 100 5 60 …

Gene 2

Gene 3

Gene 4

….

Gene Regulatory Networks (GRN)

Bar-Joseph et al., 2003

GRN of yeast in rich mediumTranscription factor (TF) regulates a gene

TF1TF1 TF2TF2 TF3TF3

Gene regulatory module

Bayesian Probabilistic Modeling

• Assign genes into co-regulated modules

• Construct regulatory relations of each module

Posterior Likelihood Prior

Gene Regulatory Network Modeling

Zhu et al., 2013

JoinJoin

Gene Regulatory Logic of a Gene Module as a Decision Tree

OneGeneModule

gene 1gene 2gene 3….….gene n

Biological Conditions (Treatments) in Columns

Transcriptionfactors and binaryregulatorytree

Low Expression

High Expression

Regulatory Tree Construction

2

2

( )

2

1

1( )

2

ij k

k

k

xs

ik j S k

p g e

Zhu et al., 2013

g1

g2

.gi

.

.gn

μ1, σ1 μ2, σ2

Gaussian Mixture

• Pick a TF• Divide conditions into

two subsets based expression states

• Calculate probability

Regulatory Tree Construction

2

2

( )

2

1

1( )

2

ij k

k

k

xs

ik j S k

p g e

Zhu et al., 2013

g1

g2

.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

2

2

( )

2

1

1( )

2

ij k

k

k

xs

ik j S k

p g e

Zhu et al., 2013

g1g2.gi..gn

Gaussian Mixture

Algorithm

Gene Re-Assignment

μ1

σ1

μ2

σ2

. . . . . . . . .

0.3 0.2 1.5 . . . . . . . .gi

RegulatoryTree ofa Module

2

2

( )

2

1

1( )

2

ij k

k

k

xs

ik j S k

p g e

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 accordingto 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

AcknowledgementsStudents• Deb Bhattacharya• Renzhi Cao• Jie Hou• Jilong Li• Matt Spencer• Trieu Tuan• Mingzhu Zhu

CollaboratorsJim 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-PDCNP-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.