Ambrosand coworkers discovered the first miRNA, lin-4 RNA, in nematode Caenorhabditis elegans in 1993 as a keyregulator of developmental timing inhibiting lin-14 and lin-28 necessary forprogression to larval stage 2 from stage 1. In 2000, Gary Rubkins lab discovered let-7 RNA temporally regulating developmentaltiminig in C. elegans bydownregulating expression of genes like lin-41and activating larval stage 4 toadult stage switch. Mutations in the heterochronic genes lin-4 and let-7 causetemporal modification in cell fates and affect developmental timing. MiRBase is the database resource for miRNA dataand the latest miRBase 21 released in 2014 contains 28645 miRNA loci from 206species and has also registered 256 precursormiRNA sequences in D.
melanogaster,1193 in mouse, 250 in C. elegans, 325in Arabidopsis thaliana and 1881 inhuman while 466 mature miRNA sequenes in D.melanogaster, 1915 in mouse, 434 in C.elegans, 427 in Arabidopsis thalianaand 2588 in Homo sapiens. Also, approximately5600 novel miRNA sequences were added to the human genome according to theresearchers from Thomas Jefferson University in Philadelphia in 2015. Thesenumbers are gradually increasing reaching tens of thousands of miRNA genes inmammalian genome as observed from deep-sequencing technologies, specializedsmall RNA isolation and cloning procedures.
The first discovered miRNAs, lin-4, let-7, were named after their phenotypes. Subsequently,miRNAs identified by sequencing or cloning were given numerical names for instance,homologues of lin-4 in other specieswere called mir-125. Furthermore, lettered suffixes were added at the end ofmiRNA sisters like mir-125a and mir-125b and numeric suffixes at the end of thesame miRNAs transcribed from multiple separate loci such as mir-125b-1 andmir-125b-2. Interestingly, mature miRNA generated from 5′ strand is namedmiR-125a-5p whereas the one generated from 3′ strand is miR-125a-3p.
ManymiRNAs are conserved in different species. Humans have at least 277 genes thatfall into 153 conserved families out of which 87 are found in Zebrafish. 33 ofthe conserved genes in Zebrafish are also observed in flies suggesting a veryimportant role in evolution. For example, miR-1 is found in the muscles ofhumans, worms and flies with very similar sequences except at the 3′ end.
Moreover, related miRNAs can be found within the species. For instance, 3different members of miR-1 family are observed in humans, one in flies and twoin worms. The evolutionarily conserved genes when impaired show higherpossibility of causing diseases as these conserved genes can connect more withother human genes. On the contrary, the most studied plant model, dicotArabidopsis has 90 conserved miRNAs that fall into 20 families conserved frommonocots, rice to dicots. Out of these 20, 12 are even found in moss.Additionally, there are hundreds of non-conserved miRNA genes. Some of thenon-conserved genes at higher levels have species-specific function in humanswhilst most of them are expressed at very low levels making them hard todetect. All these studies on conservation patterns show that miRNAs play anessential role in the regulation of the development of species.
Moreover, discoveryof the conserved miRNA-targets in multiple species can help to identify corepathways and mechanisms of species development.As per the latest miRBase data, 86 experiments have beencarried out so far for all tissues in Homosapeins, 50 in D. melanogaster,and 21 in C. elegans. Some of theidentified miRNAs exhibittissue specific or cell specific expression pattern that helps indifferentiation and maintenance of tissue or cellular identity for instance, miR-129/219/330 in brain with minimalor no expression in other tissues, significant expression of miR-122a in liverwith no expression in non-liver tissues but minute expression in brain andthymus, etc.
However, brain-specific miRNAs, miR-135 and miR-183 are expressedin some non-brain tissues and pancreas islet-specific miR-375 in organs linedwith epithelium suggesting tissue-specificity as well as general abundance ofmiRNAs. Half ofthe tissue-specific miRNAs were revealed to be clustered miRNAs like four miRNA genes fixed in the Hox gene clusters of Hox A, B,C and D are miR-196b, miR-10a, miR-196-2 and miR-10b respectively sharingexpression patterns and regulatory control of transcription as observed from insitu hybridizationand histochemical staining of miR-10a and Hoxb4. Transcription factorregulatory networks control gene expression by binding to the promoter regionsof miRNAs. MiR-208, cardiac specific miRNA, found within the introns of alphamyosin heavy chain (MHC) genes control and downregulate expression of miR-208bin Beta-MHC host gene.
In addition to the healthy individuals, the tissue-specific miRNAs arealso involved in various human diseases like diabetes, cancer, andcardiovascular disease for instance; miR-15a and miR-16-1 found at fragilesites in B cell lymphocytic leukemia patient.