Faq & help

Graphical Abstract

miRIAD in its newest version was designed to support miRNA research, especially when investigating intragenic miRNAs, i.e. miRNAs who are co-localized with protein-coding genes.

Multiple species: The integration of miRNA, mRNA, and poly(A) sequencing data for multiple species allows the investigation of miRNA - host gene and miRNA - target gene interactions on an evolutionary level. For example, MCM7 contains three oncoMirs (miR-106b, miR-93, miR-25). Interestingly, miR-93-3p correlates positively with its host gene expression in rhesus and mouse, but has a significant negative correlation across tissue expression in human.

Gene and miRNA expression: The expression of genes and miRNAs can help greatly when choosing a biological model for a study. For example, both MAP2K4 and its intronic miRNA miR-744 yield strong expression in neuronal tissue. Hence, a biological model to study their function might take this into consideration, focusing choosing cell lines with neuronal origin, for example.

Host gene miRNA correlation: The correlation of the expression of host gene and intragenic miRNA across multiple tissues is important to assess when looking for coregulated transcripts. It also may indicate direct negative feedback, in case host gene and miRNA correlate negatively, as might be the case for MCM7 and its intronic miRNA miR-25 and miR-93.

3' UTR visualization: miRIAD now displays a novel and interactive representation of the 3' UTR of protein coding genes. It shows alternative polyadenylation sites, lets the user display potential miRNA target interactions and visualize different UTR isoform expression across tissues. For example, human ZFR is targeted by its intronic miRNA miR-579. However, there are multiple UTR isoforms, suggesting that in brain, for example, about 50% of transcripts might be subject to a direct negative feedback.

Interactive network analysis: In many cases, researchers are interested in a set of genes rather than a single molecule. The identification of miRNAs with relevant impact on this gene set is often times challenging. Therefore, miRIAD allows to visualize the relationship between the genes to localize the hubs in this network. It will also calculate a network target enrichment score to identify miRNAs that target more genes than expected within the network. For example, the following gene signature known to be relevant for colorectal cancer prognosis NOTCH2, ITPRIP, FRMD6, GFRA4, OSBPL9,CPXCR1, SORCS2, PDC, C12orf66, SLC38A9, OR10H5, TRIP13, MRPL52, DUSP21, BRCA1, ELTD1, SPG7, LASS6, DUOX2 [1] identifies miR-150 as an interesting target that indeed has been published to be a protective against colorectal cancer [2].

Overview

microRNAs (miRNAs) are short (~22 nt) non-coding RNAs that play key regulatory roles in a variety of cellular processes by coordinating gene expression. miRNAs may be located in intergenic regions ("intergenic miRNAs") or mapped to intragenic loci of protein coding genes (namely "host genes"). Around 50% of the mammalian miRNAs reside within introns of protein coding genes [3-6]. Most of human miRNAS (%) are of the same orientation as their host genes. As a consequence, increasing evidence has shown that intronic miRNAs may be co-transcribed with their host genes [4, 7, 8], leading to important functional implications for particular regulatory gene networks.

What is miRIAD?

miRIAD is a web search tool developed with the primary purpose of integrating relevant information concerning intragenic miRNAs and their host genes. Taking into account that the relationship between the expression of a gene and its intragenic miRNA may represent an important component in the study of specific regulatory pathways, we aim to make miRIAD a useful tool for researchers working in the field.

How do I search for my gene or microRNA of interest?

We have implemented a flexible search engine that allows users to search for reference annotated genes and miRNAs annotated in miRBase. Important notes on searching are outlined below:

• Searches are case insensitive.
• If you want to search for a particular Gene, search-terms like the following are accepted:
  1. Official symbol: LARP7, TP53, etc.
     Ensembl: ENSG00000174720, ENSG00000141510, etc.
     Entrez: 51574, 7157, etc.
     Other aliases: PIP7S, p53, etc.
     HGNC: 24912, 11998, etc.
     Gene Full Name: La ribonucleoprotein domain family, member 7, tumor protein p53, etc.
  2. In order to search within a gene's description (gene full name), you should double-quote the search-terms, for example: "tumor protein", "cadherin type 2", "membrane phosphatase", etc.
  3. You can also search for multiple queries at once, separated by spaces. Ex: TP53 LARP7, etc.
     However, the list of results is of either of gene records or mirna records, not both.
     In other words, search for gene-terms and miRNA-terms separatedly.
  4. Try non-exact official names, then you will get all genes that match with your query. Ex: P53, BRCA, LARP, etc.
  5. If queries are numbers, searches will be on Entrez Ids.
  6. You can run a network search by starting with a colon followed by gene symbols, for example: ":AKT1 AKT2 AKT3 SREBF1"
• If you want to search for a particular microRNA, the following inputs are accepted:
  1. Mirbase symbol: hsa-mir-367, hsa-mir-302b, etc.
     Mirbase accession: MI0000775, MI0000772, etc.
  2. You can also search for multiple queries at once, separated by spaces. Ex: hsa-mir-367 hsa-mir-302b, etc.
  3. Try non-exact names, then you will get all miRNAs that match with your query-term. Ex: let-7, mir-21, etc.
  4. You do not need to worry about case-sensitivity and dashes in miRNA queries. Ex: mir19, mir367, miR-367, MIR367, etc.
  5. In valid cases, you can also search by official symbol. Ex: MIR1-1, MIR1321, etc.

The icon indicates that a particular gene is a host of an intragenic microRNA or a particular miRNA is intragenic.

What do the individual elements in the gene representation view mean?

The miRIAD webtool presents genes as depicted below. The first gene representation is a summarized representation, based on annotated regions of the individual RefSeq transcripts shown below, followed by intragenic miRNAs (darkblue = host gene has seed site for its intragenic miRNA). A separate figure below represents all 3´ untranslated regions including alternative polyadenylation sites, APA motifs, miRNA binding sites, and sites of high similarity to the full miRNA sequence.

What can I do with the network view?

Many times, one is not interested in a specific interaction between a miRNA and a target, but in the impact of a miRNA on a network. For example, if the result of an experiment yields ten genes that are differentially regulated, it is useful to show the relationship between those genes. Therefore, as depicted in the graphic representation below, miRIAD allows to visualize potential interactions between members of the network (regular blue nodes). Interactions can be filtered by score or data source. If the network contains host genes (red nodes), one can also visualize, which genes within this network are potential targets of the respective intragenic miRNA. Additionally, all miRNAs will be scanned for seed site over- or underrepresentation within the network. You can load the example shown below here.

What is the source of the data?

The miRIAD database references annotated genes from human genome (hg38) and miRNAs annotated from miRBase (version 21). The mapping of intragenic miRNAs was performed according to Hinske et al. 2010.

The protein-protein interaction dataset was downloaded from HPRD

miRNA target information is seed based according to TargetScan

The gene expression data was obtained for six tissues from Brawand et al. 2011. Reads were mapped on the human genome (hg38) using TopHat/Bowtie with default parameters. Expression values were normalized as FPKM (fragments per kilobase per million). The miRNA expression data was obtained for five tissues from Meunier et al. 2013. After trimming adapter sequences, reads were mapped on the human genome (hg38) using Bowtie 0.12.7 allowing for no mismatches. Read counts for each miRNA were normalized as CPM (counts per million). For convenience, we show the normalized expression data both in log2-transformed and untransformed scales.

Can I download data for local use?

Yes. You can download data in table format (fields separated by tabs) in the download page, so you can use it freely. If you need data not provided in miRIAD, please contact us.

Questions or suggestions?

We really appreciate user's feedbacks. If you have questions or want to suggest improvements for miRIAD, please contact us.

How to cite miRIAD?

1. miRIAD – integrating microRNA Inter- And intragenic Data. Ludwig Christian Hinske, Hugo A. M. Torres, Camila M. Lopes-Ramos, Jens Heyn, Lucila Ohno-Machado, Simone Kreth, Pedro A. F. Galante. Submitted.
2. Hinske LC, Galante PA, Kuo WP, Ohno-Machado L. A potential role for intragenic miRNAs on their host's interactome. BMC Genomics 2010, 11:553.

References

1. Abdul NA, Mokhtar NM, Harun R, Mollah MH, Rose IM, Sagap I, Tamil AM, Ngah WZ, Jamal R. A 19-Gene expression signature as a predictor of survival in colorectal cancer. BMC Medical Genomics 2016, 9:58.
2. Feng J, Yang Y, Zhang P, Wang F, Ma Y, Qin H, Wang Y. miR-150 functions as a tumour suppressor in human colorectal cancer by targeting c-Myb. J Cell Mol Med 2014, 18(10):2125-34.
3. Hinske LC, Galante PA, Kuo WP, Ohno-Machado L. A potential role for intragenic miRNAs on their host's interactome. BMC Genomics 2010, 11:553.
4. Rodriguez,A., Griffiths-Jones,S., Ashurst,J.L and Bradley, A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 2004, 14:1902–1910.
5. Ozsolak,F., Poling,L.L., Wang,Z., Liu,H., Liu,X.S., Roeder,R.G., Zhang,X., Song,J.S. and Fisher,D.E. Chromatin structure analyses identify miRNA promoters. Genes Dev. 2008, 22:3172–3183.
6. Monteys,A.M., Spengler,R.M., Wan,J., Tecedor,L., Lennox,K.A., Xing,Y. and Davidson,B.L. Structure and activity of putative intronic miRNA promoters. RNA 2010, 16:495–505.
7. Baskerville,S. and Bartel,D.P. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 2005, 11:241–247.
8. Ronchetti,D., Lionetti,M., Mosca,L., Agnelli,L., Andronache,A., Fabris,S., Deliliers,G.L. and Neri,A. (2008) An integrative genomic approach reveals coordinated expression of intronic miR-335, miR-342, and miR-561 with deregulated host genes in multiple myeloma. BMC Med. Genomics 2008 1, 37.

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