Genome-Wide Survey of MicroRNA - Transcription Factor Feed-Forward

 Regulatory Circuits in Human

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

In this work, we describe a computational framework for the genome-wide identification and characterization of mixed transcriptional/post-transcriptional regulatory circuits in humans. We concentrated in particular on feed-forward loops (FFL), in which a master transcription factor regulates a microRNA, and together with it, a set of joint target protein coding genes. The circuits were assembled with a two step procedure. We first constructed separately the transcriptional and post-transcriptional components of the human regulatory network by looking for conserved over-represented motifs in human and mouse promoters, and 3'-UTRs. Then, we combined the two subnetworks looking for mixed feed-forward regulatory interactions, finding a total of 638 putative (merged) FFLs. In order to investigate their biological relevance, we filtered these circuits using three selection criteria: (I) GeneOntology enrichment among the joint targets of the FFL, (II) independent computational evidence for the regulatory interactions of the FFL, extracted from external databases, and (III) relevance of the FFL in cancer. Most of the selected FFLs seem to be involved in various aspects of organism development and differentiation. We finally discuss a few of the most interesting cases in detail.

Related collections

Most cited references 32

Record: found
Abstract: found
Article: not found

Prediction of mammalian microRNA targets.

Benjamin Lewis, I-hung Shih, Matthew W Jones-Rhoades … (2003)

MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.

0 comments Cited 1050 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Network motifs in the transcriptional regulation network of Escherichia coli

Shai S Shen-Orr, Ron Milo, Shmoolik Mangan … (2002)

Little is known about the design principles of transcriptional regulation networks that control gene expression in cells. Recent advances in data collection and analysis, however, are generating unprecedented amounts of information about gene regulation networks. To understand these complex wiring diagrams, we sought to break down such networks into basic building blocks. We generalize the notion of motifs, widely used for sequence analysis, to the level of networks. We define 'network motifs' as patterns of interconnections that recur in many different parts of a network at frequencies much higher than those found in randomized networks. We applied new algorithms for systematically detecting network motifs to one of the best-characterized regulation networks, that of direct transcriptional interactions in Escherichia coli. We find that much of the network is composed of repeated appearances of three highly significant motifs. Each network motif has a specific function in determining gene expression, such as generating temporal expression programs and governing the responses to fluctuating external signals. The motif structure also allows an easily interpretable view of the entire known transcriptional network of the organism. This approach may help define the basic computational elements of other biological networks.

0 comments Cited 820 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2.

Yong Zhao, Joshua F Ransom, Ankang Li … (2007)

MicroRNAs (miRNAs) are genomically encoded small RNAs used by organisms to regulate the expression of proteins generated from messenger RNA transcripts. The in vivo requirement of specific miRNAs in mammals through targeted deletion remains unknown, and reliable prediction of mRNA targets is still problematic. Here, we show that miRNA biogenesis in the mouse heart is essential for cardiogenesis. Furthermore, targeted deletion of the muscle-specific miRNA, miR-1-2, revealed numerous functions in the heart, including regulation of cardiac morphogenesis, electrical conduction, and cell-cycle control. Analyses of miR-1 complementary sequences in mRNAs upregulated upon miR-1-2 deletion revealed an enrichment of miR-1 "seed matches" and a strong tendency for potential miR-1 binding sites to be located in physically accessible regions. These findings indicate that subtle alteration of miRNA dosage can have profound consequences in mammals and demonstrate the utility of mammalian loss-of-function models in revealing physiologic miRNA targets.