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Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species.

ABSTRACT: Mammalian preimplantation embryonic development (PED) is thought to be governed by highly conserved processes. While it had been suggested that some plasticity of conserved signaling networks exists among different mammalian species, it was not known to what extent modulation of the genomes and the regulatory proteins could "rewire" the gene regulatory networks (GRN) that control PED. We therefore generated global transcriptional profiles from three mammalian species (human, mouse, and bovine) at representative stages of PED, including: zygote, two-cell, four-cell, eight-cell, 16-cell, morula and blastocyst. Coexpression network analysis suggested that 40.2% orthologous gene triplets exhibited different expression patterns among these species. Combining the expression data with genomic sequences and the ChIP-seq data of 16 transcription regulators, we observed two classes of genomic changes that contributed to interspecies expression difference, including single nucleotide mutations leading to turnover of transcription factor binding sites, and insertion of cis-regulatory modules (CRMs) by transposons. About 10% of transposons are estimated to carry CRMs, which may drive species-specific gene expression. The two classes of genomic changes act in concert to drive mouse-specific expression of MTF2, which links POU5F1/NANOG to NOTCH signaling. We reconstructed the transition of the GRN structures as a function of time during PED. A comparison of the GRN transition processes among the three species suggested that in the bovine system, POU5F1's interacting partner SOX2 may be replaced by HMGB1 (a TF sharing the same DNA binding domain with SOX2), resulting in rewiring of GRN by a trans change.

SUBMITTER: Xie D

PROVIDER: S-EPMC2877577 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species.

Xie Dan D Chen Chieh-Chun CC Ptaszek Leon M LM Xiao Shu S Cao Xiaoyi X Fang Fang F Ng Huck H HH Lewin Harris A HA Cowan Chad C Zhong Sheng S

Genome research 20100310 6

Mammalian preimplantation embryonic development (PED) is thought to be governed by highly conserved processes. While it had been suggested that some plasticity of conserved signaling networks exists among different mammalian species, it was not known to what extent modulation of the genomes and the regulatory proteins could "rewire" the gene regulatory networks (GRN) that control PED. We therefore generated global transcriptional profiles from three mammalian species (human, mouse, and bovine) a ...[more]

PMID: 20219939

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Project description:Gene regulatory networks (GRNs) play a central role in systems biology, especially in the study of mammalian organ development. One key question remains largely unanswered: Is it possible to infer mammalian causal GRNs using observable gene co-expression patterns alone? We assembled two mouse GRN datasets (embryonic tooth and heart) and matching microarray gene expression profiles to systematically investigate the difficulties of mammalian causal GRN inference. The GRNs were assembled based on > 2,000 pieces of experimental genetic perturbation evidence from manually reading > 150 primary research articles. Each piece of perturbation evidence records the qualitative change of the expression of one gene following knock-down or over-expression of another gene. Our data have thorough annotation of tissue types and embryonic stages, as well as the type of regulation (activation, inhibition and no effect), which uniquely allows us to estimate both sensitivity and specificity of the inference of tissue specific causal GRN edges. Using these unprecedented datasets, we found that gene co-expression does not reliably distinguish true positive from false positive interactions, making inference of GRN in mammalian development very difficult. Nonetheless, if we have expression profiling data from genetic or molecular perturbation experiments, such as gene knock-out or signalling stimulation, it is possible to use the set of differentially expressed genes to recover causal regulatory relationships with good sensitivity and specificity. Our result supports the importance of using perturbation experimental data in causal network reconstruction. Furthermore, we showed that causal gene regulatory relationship can be highly cell type or developmental stage specific, suggesting the importance of employing expression profiles from homogeneous cell populations. This study provides essential datasets and empirical evidence to guide the development of new GRN inference methods for mammalian organ development.

Project description:Gene set and sub-network enrichment analysis provides an integrated approach for identifying gene regulatory networks underlying development. Anuran development is a coordinated process, and levels of mRNA are first dominated by maternally deposited genes, followed by active transcription of embryonic genes as the embryo undergoes morphogenesis and organ formation. The objectives of this study were to characterize early gene regulatory networks underlying Silurana tropicalis development. A custom Agilent 4 x 44 K microarray was developed to characterize networks during early development (1, 17, 36, 96 hpf). Cluster analysis revealed that each stage showed unique gene expression profiles and that 1 hpf was most different than the other three stages. There were > 8000 unique gene probes (p<0.01, FDR = 5%) that were differentially expressed between 1 hpf (2 cell stage) and 17 hpf and > 2000 gene probes differentially expressed between 36 hpf and 96 hpf. Genes higher in abundance (>100-fold) at 1 hpf compared to 17 hpf included oocyte-specific histone RNA stem-loop-binding protein 2, mitogen-activated protein kinase 14, and cyclin B5, suggesting these transcripts are maternally inherited or actively transcribed at fertilization. Gene ontology revealed that genes involved in nucleosome assembly, cell division, pattern specification, neurotransmission, and general metabolism were increasingly regulated throughout development, consistent with active development. In the period between 17-36 hpf, gene networks that play a role in organogenesis and organ function, including those related to the heart (heart morphogenesis, central nervous system (olfactory bulb development, dopamine metabolism), and kidney (renal reabsorption, water balance) were activated while between 36-96 hpf, networks involving in gut development, immune responses, lipid metabolism, hormone signaling, and brain development were prevalent. This study increases understanding of the spatiotemporal S. tropicalis embryonic development using gene regulatory networks. Gene expression analysis was performed with four biological replicates for four developmental stages (n = 16). Stages were NF stages 2, 16, 34, and 46.

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Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species.

Publications

Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species.

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