MicroRNAs preferentially target the genes with high transcriptional regulation complexity

doi:10.1016/j.bbrc.2006.11.080

Biochemical and Biophysical Research Communications

Volume 352, Issue 3, 19 January 2007, Pages 733-738

https://doi.org/10.1016/j.bbrc.2006.11.080 Get rights and content

Abstract

Over the past few years, microRNAs (miRNAs) have emerged as a new prominent class of gene regulatory factors that negatively regulate expression of approximately one-third of the genes in animal genomes at post-transcriptional level. However, it is still unclear why some genes are regulated by miRNAs but others are not, i.e. what principles govern miRNA regulation in animal genomes. In this study, we systematically analyzed the relationship between transcription factors (TFs) and miRNAs in gene regulation. We found that the genes with more TF-binding sites have a higher probability of being targeted by miRNAs and have more miRNA-binding sites on average. This observation reveals that the genes with higher cis-regulation complexity are more coordinately regulated by TFs at the transcriptional level and by miRNAs at the post-transcriptional level. This is a potentially novel discovery of mechanism for coordinated regulation of gene expression. Gene ontology analysis further demonstrated that such coordinated regulation is more popular in the developmental genes.

Section snippets

Materials and methods

Datasets used in this study. A dataset representing three transcription factors, OCT4, NANOG, and SOX2 and their target genes in human embryonic stem cells was obtained from Boyer et al. [9]. The regulatory relationships of the three transcription factors and their target genes are listed in Supplementary Text File S1.

The genome-wide computationally predicted human miRNA target genes were obtained from Krek et al. [10]. There were a total of 6243 genes regulated by 168 miRNAs. The miRNAs and

Results and discussion

To study how miRNAs and TFs coordinately regulate genes in the human genome, we first took a dataset which represents the regulatory relations between the three TFs, OCT4, NANOG, and SOX2, and their target genes in human embryonic stem cells [9]. The regulatory relationships between the three TFs (OCT4, NANOG, and SOX2) and their target genes were determined through ChIP-chip analysis (chromatin immunoprecipitation coupled with DNA microarray) [9]. The three TFs regulate a total of 2046 genes.

Acknowledgments

This work was partially supported by the Genomics and Health Initiative, National Research Council Canada. We thank Doreen Harcus for reading the manuscript and correcting grammar mistakes.

References (39)

D.P. Bartel
MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)
B.R. Cullen
Transcription and processing of human microRNA precursors
Mol. Cell
(2004)
S.M. Hammond
MicroRNAs as oncogenes
Curr. Opin. Genet. Dev.
(2006)
L.A. Boyer et al.
Core transcriptional regulatory circuitry in human embryonic stem cells
Cell
(2005)
B.P. Lewis et al.
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets
Cell
(2005)
A. Stark et al.
Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution
Cell
(2005)
W.H. Li et al.
Expression divergence between duplicate genes
Trends Genet.
(2005)
Z. Zhang et al.
How much expression divergence after yeast gene duplication could be explained by regulatory motif evolution?
Trends Genet.
(2004)
V. Ambros
The functions of animal microRNAs
Nature
(2004)
V.N. Kim
MicroRNA biogenesis: coordinated cropping and dicing
Nat. Rev. Mol. Cell Biol.
(2005)

M.A. Carmell et al.

RNase III enzymes and the initiation of gene silencing

Nat. Struct. Mol. Biol.

(2004)

G. Meister et al.

Mechanisms of gene silencing by double-stranded RNA

Nature

(2004)

S. Griffiths-Jones et al.

Rfam: annotating non-coding RNAs in complete genomes

Nucleic Acids Res.

(2005)

A. Krek et al.

Combinatorial microRNA target predictions

Nat. Genet.

(2005)

D. Cora et al.

Ab initio identification of putative human transcription factor binding sites by comparative genomics

BMC Bioinformatics.

(2005)

X. Xie et al.

Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals

Nature

(2005)

T. Beißbarth et al.

GOstat: find statistically overrepesented gene ontologies within a group of genes

Bioinformatics

(2004)

A.J. Enright et al.

MicroRNA targets in Drosophila

Genome Biol.

(2003)

B. John et al.

Human MicroRNA targets

PLoS Biol.

(2004)

Cited by (114)

Integrated mRNA-Seq and miRNA-Seq analysis reveals the microRNAs-transcription factor-mRNA regulatory network of pearl gentian grouper under acute hypoxia
2024, Aquaculture
Pearl gentian grouper (Epinephelus lanceolatus ♂ × Epinephelus fuscoguttatus ♀) is a hybrid fish with high commercial value and it has the highest yield among groupers farmed along the southeastern coast of China. However, hypoxia is not only a key factor to limit the healthy growth and survival of the grouper under high-density and intensive farming, but also hinders the rapid development of its aquaculture industry. In this study, we analyzed the transcriptomic characteristics of pearl gentian grouper under acute hypoxic stress (DO 0.5 mg/L) for 1 h, 3 h, 6 h, and 9 h and normoxic condition (DO 5.5 mg/L) to determine the biological processes and molecular regulatory mechanisms underlying the response to hypoxia. By an integrated analysis of mRNA and miRNA sequencing data, we constructed a microRNA-transcription factor-mRNA regulatory network containing 52 miRNAs, 17 transcription factors, and 72 genes. During acute hypoxic stress, these key molecules were involved in several important biological processes. The activation of anaerobic glycolysis and fatty acid metabolism, cell cycle arrest contributed to grouper survival under hypoxia. Based on analyses of gene expression profiles, hypoxic stress for 3–6 h and 9 h were identified as two critical periods with significantly altered physiologic and metabolic responses in pearl gentian grouper (e.g., the transformation of energy metabolism patterns and severe oxidative stress). These results indicate that intervention measures should be implemented within 6 h of acute hypoxia in high-density and intensive farming of the grouper. Thus, our study contributes to a deeper understanding of the molecular regulatory mechanism of pearl gentian grouper adaption to acute hypoxia and provide an important scientific basis for the management of hypoxia in high-density and intensive farming practices.
Aging in Rodents
2019, Encyclopedia of Biomedical Gerontology: Volume 1-3
This article gives an overview about the aging in rodents and how rodents can be used for aging modelling. The article starts with more general consideration about the modelling and some basic background. It is followed by the review of the most common progeroid syndromes along with the molecular mechanisms of aging. Then the effect of caloric restriction is described in deeper details. And finally, the role of transposable elements and the role of their activation during aging is described. Therefore, present article covers broadly the modelling of aging in the rodents with some more detailed overviews for the mechanisms explaining the potential interventions to modify the aging and aging related problems.
Aging in rodents
2019, Encyclopedia of Biomedical Gerontology
This article gives an overview about the aging in rodents and how rodents can be used for aging modelling. The article starts with more general consideration about the modelling and some basic background. It is followed by the review of the most common progeroid syndromes along with the molecular mechanisms of aging. Then the effect of caloric restriction is described in deeper details. And finally, the role of transposable elements and the role of their activation during aging is described. Therefore, present article covers broadly the modelling of aging in the rodents with some more detailed overviews for the mechanisms explaining the potential interventions to modify the aging and aging related problems.
miRNA mediated regulation of NAC transcription factors in plant development and environment stress response
2017, Plant Gene
NAC genes comprise one of the largest families of plant transcription regulators that are known to play crucial roles in various developmental processes and stress responses. Evolutionary expansion of the gene family in land plants probably added to the functional diversity of the gene family. The ongoing research has analyzed the differential expression patterns of the NAC transcription factors under various stresses for determining their plausible role during adaptive stress response in plants. However, the complex molecular mechanism regulating NAC gene expression and function is still elusive. The discovery of miRNAs, as a novel class of regulatory factors, has shed new light on the regulatory mechanisms that define the functional domains of the transcription factors. In this context studies on miRNA-mediated regulation of NAC gene expression in plant development have provided critical evidence for multi-layered control of the transcription factors. The review describes the divergent role of NAC transcription factors, which were initially thought to be only involved in vasculature development in plants. The structural features of the NAC transcription factors and the evolution of the gene family have also been discussed. Special focus is placed on the regulation of NAC-TFs by miRNAs to understand the developmental networks operating in the plants in response to abiotic stress and hormone cues.
Inferring the determinants of protein evolutionary rates in mammals
2016, Gene
Understanding the determinants of protein evolutionary rates is one of the most fundamental evolutionary questions. Previous studies have revealed that many biological variables are tightly associated with protein evolutionary rates in mammals. However, the dominant role of these biological variables and their combinatorial effects to evolutionary rates of mammalian proteins are still less understood. In this work, we derived a quantitative model to correlate protein evolutionary rates with the levels of these variables. The result showed that only a small number of variables are necessary to accurately predict protein evolutionary rates, among which miRNA regulation plays the most important role. Our result suggested that biological variables are extensively interrelated and suffer from hidden redundancies in determining protein evolutionary rates. Various variables should be considered in a natural ensemble to comprehensively assess the determinants of protein evolutionary rate.
A novel framework for inferring condition-specific TF and miRNA co-regulation of protein-protein interactions
2016, Gene
Citation Excerpt :
Given the important roles of TFs and miRNAs, it is of great interest to have the unified gene regulatory networks involving both TFs and miRNAs for understanding biological processes. Some studies (Shalgi et al., 2007; Cui et al., 2007a; Le Béchec et al., 2011; Roqueiro et al., 2012; Le et al., 2013; Guo et al., 2014; Hamed et al., 2015) have investigated TF and miRNA co-regulatory networks, but they have not considered the downstream protein–protein interactions (PPIs), which are indeed critical to most biological processes. PPIs are at the core of the entire interactomics system of all living cells, and PPI networks can provide insight into the causes of diseases (Sanz-Pamplona et al., 2012).
Recent studies have shown that transcription factors (TFs) and microRNAs (miRNAs), while independently regulate their downstream targets, collaborate with each other to regulate gene expression. However, their synergistic roles in protein–protein interactions (PPIs) remain mostly unknown. In this paper, we present a novel framework (called CoRePPI) for inferring TF and miRNA co-regulation of PPIs. Particularly, CoRePPI is aimed at discovering the co-regulation specific to a condition of interest, by using heterogeneous data, including miRNA and messenger RNA (mRNA) expression profiles, putative miRNA targets, TF targets and PPIs. CoRePPI firstly finds the network motifs indicating the co-regulation of PPIs by TFs and miRNAs in tumor and normal conditions separately. Then by identifying the differential motifs found in one condition but not in the other, it builds the networks consisting of TFs, miRNAs and their co-regulated PPIs specific to different conditions respectively. To validate CoRePPI, we apply it to the Pan-Cancer dataset which includes the expression profiles of 12 cancer types from TCGA. Through network topology analysis, we found that the tumor and normal CoRePPI networks are scale-free. Furthermore, the results of differential and intersected network analysis between the tumor and normal CoRePPI networks suggest that only a small fraction of the regulatory relationships between TFs and miRNAs are conserved in both conditions but they co-regulate different downstream PPIs in tumor and normal conditions; and in different conditions the majority of the regulatory relationships between TFs and miRNAs are different although they may regulate the same PPIs in their respective conditions. The CoRePPI sub-networks constructed for the three types of cancers (breast cancer, lung cancer and ovarian cancer) are all scale-free, and the intersection of these CoRePPI sub-networks can be utilized as the biomarker CoRePPI sub-network of the three types of cancers. The PPI enrichment analyses of the tumor and normal CoRePPI networks suggest that the co-regulating TFs and miRNAs are significantly associated with the specific biological processes, diseases and pathways. In addition, comparing with the two non-condition-specific approaches, the tumor CoRePPI network is found to have the most enriched cancer-related PPIs. Altogether, the results uncover the combined regulatory patterns of TFs and miRNAs on the PPIs, and may provide new insights for research in cancer-associated TFs and miRNAs.

View all citing articles on Scopus

¹: These authors contributed equally to this work.

View full text

MicroRNAs preferentially target the genes with high transcriptional regulation complexity

Abstract

Section snippets

Materials and methods

Results and discussion

Acknowledgments

Cell

Mol. Cell

Curr. Opin. Genet. Dev.

Cell

Cell

Cell

Trends Genet.

Trends Genet.

The functions of animal microRNAs

Nature

MicroRNA biogenesis: coordinated cropping and dicing

Nat. Rev. Mol. Cell Biol.

RNase III enzymes and the initiation of gene silencing

Nat. Struct. Mol. Biol.

Mechanisms of gene silencing by double-stranded RNA

Nature

Rfam: annotating non-coding RNAs in complete genomes

Nucleic Acids Res.

Combinatorial microRNA target predictions

Nat. Genet.

Ab initio identification of putative human transcription factor binding sites by comparative genomics

BMC Bioinformatics.

Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals

Nature

GOstat: find statistically overrepesented gene ontologies within a group of genes

Bioinformatics

MicroRNA targets in Drosophila

Genome Biol.

Human MicroRNA targets

PLoS Biol.