Characterizing dynamic regulatory programs in mouse lung development and their potential association with tumourigenesis via miRNA-TF-mRNA circuits
© Liu et al.; licensee BioMed Central Ltd. 2013
Published: 17 December 2013
In dynamic biological processes, genes, transcription factors(TF) and microRNAs(miRNAs) play vital regulation roles. Many researchers have focused on the transcription factors or miRNAs in transcriptional or post transcriptional stage, respectively. However, the transcriptional regulation and post transcriptional regulation is not isolated in the whole dynamic biological processes, there are few reserchers who have tried to consider the network composed by genes, miRNAs and TFs in this dynamic biological processes, especially in the mouse lung development. Moreover, it is widely acknowledged that cancer is a kind of developmental disorders, and some of pathways involved in tissue development might be also implicated in causing cancer. Although it has been found that many genes differentially expressed during mouse lung development are also differentially expressed in lung cancer, very little work has been reported to elucidate the combinational regulatory programs of such kind of associations.
In order to investigate the association of transcriptional and post-transcriptional regulating activities in the mouse lung development, we define the significant triple relations among miRNAs, TFs and mRNAs as circuits. From the lung development time course data GSE21053, we mine 142610 circuit candidates including 96 TFs, 129 miRNAs and 13403 genes. After removing genes with little variation along different time points, we finally find 64760 circuit candidates, containing 8299 genes, 50 TFs, and 118 miRNAs in total. Further analysis on the circuits shows that the circuits vary in different stages of the lung development and play different roles. By investigating the circuits in the context of lung specific genes, we identify out the regulatory combinations for lung specific genes, as well as for those lung non-specific genes. Moreover, we show that the lung non-specific genes involved circuits are functionally related to the lung development. Noticing that some tissue developmental systems may be involved in tumourigenesis, we also check the cancer genes involved circuits, trying to find out their regulatory program, which would be useful for the research of lung cancer.
The relevant transcriptional or post-transcriptional factors and their roles involved in the mouse lung development are both changed greatly in different stages. By investigating the cancer genes involved circuits, we can find miRNAs/TFs playing important roles in tumour progression. Therefore, the miRNA-TF-mRNA circuits can be used in wide translational biomedicine studies, and can provide potential drug targets towards the treatment of lung cancer.
Although it is not completely understood what and how many factors play main roles in the process of lung development, several factors that invovle in the dynamic process and play important roles have been confirmed by the biologist. Through analysis of gene expression data at different stages of lung development in the field of molecular biology, a series of novel temporal regulations, target genes, transcription factors, and candidate regulatory pathways have been observed during these dynamic biological processions [1, 2]. The mammalian lung development can be divided into six stages, ranging from embryos to mature lung [1, 3]. At these different stages of lung development, the involved regulatory elements should include both housekeeping and stage-specific ones.
It is well known that transcription factors (TFs) and microRNAs (miRNAs) are key regulators for gene expression regulation in high eukaryotes. The transcription factor play a key role in the transcription process which controls the activity of a gene by determining whether the gene's DNA is transcribed. The first step of the process of transcription is to convert the gene's DNA into a complementary coding mRNA molecule; then in the second step, the mRNA molecule is translated as an amino acid sequence of a protein . While, miRNAs are a class of short RNA (21-24 nt) sequences that can regulate the expression of target genes at the post-transcriptional level . Based on the pairing of miRNAs and their target sites on corresponding mRNAs, the complexes can inhibit translation by either degrading the mRNAs, or by blocking translation without degrading the targets .
There have been many studies focusing on investigating the functions of miRNAs or TFs, respectively. For examples, Dong et al. investigated the dynamical miRNA and mRNA regulation patterns for lung development by using statistical and computational methods . Bandyopadhyay et al. obtained a global perspective of miRNA dysregulation in multiple cancer types by analyzing the differential expression patterns of specific miRNAs in cancer tissues . There are also some studies considering the miRNA regulatory network [8–10] or TFs and target genes regulatory networks . As a result, many computational tools have been proposed to predict the miRNA-mRNA regulations (EMBL , Miranda , SNMNMF[14, 15], PicTar , mirConnX , and TargetScan ), or the TF-mRNA regulations (TRRD, JASPAR, and TRANSFAC [21, 22]). Recently there are several attempts to discover the combinational links between miRNAs, TFs and target mRNAs (genes) [23–26], however, it is obviously that not enough attentions are paid on the regulatory combinations to understand the molecular mechanism of the complicated biological processes. In our preliminary version of this work , we have proposed a methodology to consider the regulatory combinations involved in the mouse lung development, and found some regulatory combinations in different lung developmental stages. Our earlier work has only considered the context of lung specific genes. However, the lung developmental process is complicated, which may be involved in not only lung specific but also lung non-specific genes and their regulators. Therefore, not just lung specific genes, but other tissue genes should also be considered to systematically investigate the regulatory mechanism of lung development.
It is widely acknowledged that cancer is a kind of complex developmental disorders, and some controlling developmental systems might also be involved in causing cancer. Lung cancer is the highest mortality cancer  and thus has recently attracted more and more attentions. Bonner et al.  have examined the genetic changes occurring during lung carcinogenesis by analyzing tissues from mice normal lungs and cancers on Affymetrix U74Av2 gene chips, and found that 24 developmentally regulated genes are aberrantly expressed in lung tumours. Kopantzev et al. [29, 30] have found that opposite differences by comparing gene expression profiles in human non-small cell lung carcinomas and in human fetal lung development. Understanding the association of the regulatory mechanisms between lung development and lung tumour might provide novel insight of the lung carcinogenesis, which is helpful for the treatment of the lung cancer.
To address above questions, in this paper we define the significant triple relation among miRNA, TF and mRNA as a circuit, and propose to detect the circuits to identify the non-trivial regulatory combinations in the lung development of mouse. Then we analyze the combinations across the lung development and find out stage-specific combinations. According to the lung specific genes collected from the tissue specific gene database TiSGeD , we further distinguish circuits specific to lung development from those irrelevant to the lung developmental process. Finally, we consider the genes that have been shown to be related to cancers in literature and investigate their involved circuitsto find out the multiple roles of miRNAs and TFs in lung development and tumour progression. Our results give a systematic view for understanding the alteration of transcriptional or post-transcriptional regulatory factors and their roles involved in the mouse lung development and tumour progression.
(1) Lung development time-course data collected from two mouse samples: GSE21053 . GSE21053 consists of GSE20152 and GSE20954, corresponding to miRNA and gene expression data respectively. The expression values are measured at seven time points: embryo day 12, 14, 16, and 18; and postnatal day 2, 10 and 30.
(2) Lung specific genes: The Tissue-Specific Genes Database (TiSGeD) . TiSGeD provides comprehensive information of genes specific to lung and other tissues collected from biomedical literatures. By setting SPM  threshold as 0.3, we extract 511 lung specific genes from TiSGeD, 455 of them are in common with GSE20954 and will be used for further study.
(3) Cancer related genes: we collect all the 487 cancer related genes from Cancer Gene Census, 118 of which are overlapped with the lung developmental genes, and 19 of which are also found to be lung specific genes.
(6) miRNA-TF pairs: circuitDB .
Extraction of miRNA-TF-mRNA circuit candidates
Detection of significant circuits relevant to lung development
where E is the mathematical expectation and μ i is the mean of vector i. We use the permutation test to evaluate the significance of the correlation and set the p-value threshold as 0.05. Only when all of three pairs in the same circuit candidate are significant, can it be regarded as a circuit at the specific period of lung development.
Results and discussion
Dynamic circuits involved in the lung development
TF overlap (Figure 5(b))
We have found that there are four TFs: BACH2, IRF1, MYC and HOXA4, which are participated in the early and late stages. BACH2 and HOXA4 are down-regulated in the early stage and up-regulated in the late stage (HOXA4 is one point time lagged); and IRF1 is up-regulated while MYC is down-regulated across all the time points (Figure 7(a)). It has been shown that Hox genes are implicated in the lung development and the patterning, and the HOXA4 and HOXA5 are likely to be involved in the patterning of the mouse lung . According to the GO term GO:0048513, IRF1 and MYC also have the function related to the organ development. It is noticeable that MYC amplification is found to be a prognostic marker of early-stage lung adenocarcinoma , and BACH2 has also been researched in the cancer treatment , which shows that the tumour has association with the developmental process.
MiRNA overlap (Figure 5(c))
We have found that there are five miRNAs participated in both the early and late stages: mmu-mir-200a, mmu-mir-200b, mmu-mir-135b, mmu-mir-494 and mmu-mir-503. They show similar expression profiles along six time points of the lung development: first down-regulated and then up-regulated (Figure 7(b)). The miR-200 family is believed to play an essential role in the tumour suppression. It has been shown to play an important role in fibrotic lung diseases . The mir-135b, mir-503b and mir-94 are also found to have relationship with lung cancer [42–44]. We think that miRNAs related to cancers may more likely participate in regulatory programs of both lung developmental stages.
Gene overlap (Figure 5(d))
We have found that there are 24 common genes roughly divided into two groups (Prdx6, B3gnt2, Car3, Cbx1, Ccdc88a, Cdh13, Cpeb1, Cth, Dclk1, Dnajc9, Fgd4, Il1rap, Ipo9, Klf4, Klhl29, Mpp7, Pde7a, Pdk4, Per1, Phf20, Plat, Rnf138, Rtn4, Tdrkh) occurring in the early and late stages (Figure 7(c)). It has been shown that most of them are related to tumours, such as Prdx6 , Cdh13 , Klf4 , and so on. Once again, we suggest that common genes in early and late stages of lung development may be more likely related to tumourigenesis even if they are not shown to be cancer genes.
Dynamic regulations of circuits in the context of lung specific genes
Specifically, we have detected out some regulators for lung non-specific genes, i.e., TF: ATF6, DBP (early), and TBP (late); miRNAs: mmu-mir-152, mmu-mir-187, mmu-mir-320, mmu-mir-326, mmu-mir-451 (early), and mmu-mir-494 (late). We think that they should have functions related to the lung development even though their regulating genes are not lung specific. For examples, ATF6 is an endoplasmic reticulum (ER) stress-regulated transmembrane transcription factor, and specific ER stress signaling transmitted by ATF6 leads to naturally occurring apoptosis during the muscle development ; DBP is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid, and urine and on the surface of many cell types; miR-320 plays a role in neuronal development. According to the functional annotations of the regulators, it seems that they can actually play roles in the lung development in an indirect way.
From Figure 10, we can see that different group of genes involved in early and late stages of the lung development, regulated by different TF-miRNA combinations. Moreover, some common genes/TFs/miRNAs involved in different stages show different functions. Gene Prdx6 is involved in one circuit in the early stage (IRF1~mmu-mir-503~Prdx6), while involved in the other two circuits containing the same miRNA (MYC~mmu-mir-19a~Prdx6, IRF1~mmu-mir-19a~Prdx6) in the late stage. Thus, in different stages of the lung development, Prdx6 may show different functions which are mainly determined by mmu-mir-503 and mmu-mir-19a, respectively.
We have also noted that mmu-mir-200a play some roles in the early stage by cooperating with MEIS1, while play other roles in the late stage by cooperating with BRCA1 together. By cooperating with different miRNAs, transcript factors BACH2, MYC or IF1 can co-regulate different genes in the early and late stages, respectively.
Functional specificities of circuits in lung development
We have found that the miRNA and the TF usually have dynamical regulation programs at different stages during mouse lung development. In particular, the involved genes usually have opposite expression profiles at different stages (Figure 4). To computationally explore the potential functions of the dynamically regulated genes in lung development, we have employed biological process and pathway analysis on the lung specific genes.
Top 10 GO biological process terms in different periods
GO:0006793~phosphorus metabolic process
GO:0006796~phosphate metabolic process
GO:0045596~negative regulation of cell differentiation
GO:0051056~regulation of small GTPase mediated signal transduction
GO:0006468~protein amino acid phosphorylation
GO:0035023~regulation of Rho protein signal transduction
GO:0007167~enzyme linked receptor protein signaling pathway
GO:0022604~regulation of cell morphogenesis
GO:0051094~positive regulation of developmental process
GO:0030030~cell projection organization
GO:0017148~negative regulation of translation
GO:0010558~negative regulation of macromolecule biosynthetic process
GO:0010608~posttranscriptional regulation of gene expression
GO:0032268~regulation of cellular protein metabolic process
GO:0031327~negative regulation of cellular biosynthetic process
GO:0051674~localization of cell
Significant pathways in different periods
mmu04810:Regulation of actin cytoskeleton
mmu04115:p53 signaling pathway
mmu05200:Pathways in cancer
mmu04060:Cytokine-cytokine receptor interaction
mmu00533:Keratan sulfate biosynthesis
In Table 2, the pathways indicated in bold have been reported to be associated with lung. For mmu04810, Actin cytoskeleton plays a role in human pulmonary artery ECS . For mmu00740, lung remodelling induced by exposure of total parenteral nutrition to ambient light is due to the interaction between vitamin C and peroxides generated by the exposure of riboflavin to light . For mmu04060, the analysis of lung adenocarcinoma tissue specimens have demonstrated that the genes involved in these biological pathways have high rates of over-expression . For mmu00230, metabolic changes in the lung as a result of ventilation-induced lung injury are reflected by an increased level of purine in the bronchoalveolar lavage fluid and that purine may, thus, serve as an early marker for ventilation-induced lung injury . For mmu00533, the pathways of Keratan sulphate biosynthesis are associated with prostate cancer and small cell lung cancer.
Investigation on cancer genes involved in circuits
In this work, we have mined and investigated the miRNA-TF-mRNA circuits involve in mouse lung development. The results have shown that the relevant transcriptional or post-transcriptional factors and their roles involved in lung development greatly vary at different stages. By considering those circuits associated with lung specific genes, we have identified out the dynamic regulatory interaction of miRNA-TF-mRNA circuits in different lung development stages. By investigating the circuits in the context of cancer genes, we have detected out some circuits related to the lung cancer, thus illustrating the association between the lung development and the tumourigenesis. Therefore, the miRNA-TF-mRNA circuits can be used in wide translational biomedicine studies, and can provide potential drug targets towards the treatment of lung cancer.
A preliminary version of this paper was published in the proceedings of IEEE ISB2012.
The publication of this article has been funded by the National Science Foundation of China (61272274, 60970063), the program for New Century Excellent Talents in Universities (NCET-10-0644), the Ph.D. Programs Foundation of Ministry of Education of China (20090141110026) and the Fundamental Research Funds for the Central Universities (6081007).
This article has been published as part of BMC Systems Biology Volume 7 Supplement 2, 2013: Selected articles from The 6th International Conference of Computational Biology. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcsystbiol/supplements/7/S2.
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