Micro RNA

miRNA
4 Oct 2017

1. definitionG14
   MicroRNAs or miRNAs, a subset of non-coding
   RNAs, are ∼22-nt long endogenously-initiated short
   RNA molecules that are considered to posttranscriptionally
   regulate the cleavage of target m-
   RNAs or just repress their translation
   
   G15
   A microRNA (abbreviated miRNA) is a small non-coding RNA
   molecule (containing about 22 nucleotides) found in plants, animals and
   some viruses, that functions in RNA silencing and post-transcriptional
   regulation of gene expression.[1][2] While the majority of miRNAs are
   located within the cell, some miRNAs, commonly known as circulating
   miRNAs or extracellular miRNAs, have also been found in
   extracellular environment, including various biological fluids and cell
   culture media.
   
   1. perbedaan dengan siRNA
      Link: https://www.dropbox.com/s/buptsslguui80gg/perbedaan%20siRNA%20dan%20miRNA.png?dl=0G15
      miRNAs resemble the small interfering RNAs (siRNAs) of the RNA
      interference (RNAi) pathway, except miRNAs derive from regions of
      RNA transcripts that fold back on themselves to form short hairpins,
      whereas siRNAs derive from longer regions of double-stranded RNA.[2]
   2. picture (G15)
      Link: https://www.dropbox.com/sh/di0tb9ktqxac0v9/AABg3dDbi9njHKJMDVkeUkXXa?dl=0
2. amountG14
   It is estimated
   that miRNAs constitute nearly 1% of all predicted
   genes in nematodes, flies and mammals
   
   g15
   The human genome may encode over 1000 miRNAs,[6][7] which are
   abundant in many mammalian cell types[8][9] and appear to target about
   60% of the genes of humans and other mammals.[10][11]
   
   Across all species, in excess of 5000 different miRNAs had been identified by March 2010.[118] Whilst short RNA sequences (50 –hundreds of base pairs) of a broadly comparable function occur in bacteria, bacteria lack true microRNAs.[119]
3. historyG14  
   The significance of miRNAs had been long overlooked   due to the limitation of technology and methodology   until its initial discovery that two miRNAs, lin-4 and   let-7, were found to control the timing of the nematode   (Caenorbabditis elegans) development through   incomplete base pairing to the 3 UTRs of the target   mRNAs to repress their translation
   
   G15
   The first miRNA was discovered in 1993 by a group led by Ambros and including Lee and Feinbaum; but additional insight into its mode of action required simultaneously published work by Ruvkun's team, including Wightman and Ha.[24][25] These groups published back-toback papers on the lin-4 gene, which was known to control the timing of C. elegans larval development by repressing the lin-14 gene. When Lee et al. isolated the lin-4 gene, they found that instead of producing an mRNA encoding a protein, it produced short non-coding RNAs, one of which was a ~22-nucleotide RNA that contained sequences partially complementary to multiple sequences in the 3' UTR of the lin-14 mRNA.[24] This complementarity was proposed to inhibit the translation of the lin-14 mRNA into the LIN-14 protein. At the time, the lin-4 small RNA was thought to be a nematode idiosyncrasy. In 2000, a second small RNA was characterized: let-7 RNA, which represses lin-41 to promote a later developmental transition in C. elegans.[26] The let-7 RNA was found to be conserved in many species, leading to the suggestion that let-7 RNA and additional "small temporal RNAs" might regulate the timing of development in diverse animals, including humans.[27] A year later, the lin-4 and let-7 RNAs were found to be part of a large class of small RNAs present in C. elegans, Drosophila and human cells.[28][29][30] The many RNAs of this class resembled the lin-4 and let-7 RNAs, except their expression patterns were usually inconsistent with a role in regulating the timing of development. This suggested that most might function in other types of regulatory pathways. At this point, researchers started using the term "microRNA" to refer to this class of small regulatory RNAs.[28][29][30] The first human disease associated with deregulaton of miRNAs was chronic lymphocytic leukemia.[46]
4. geneG14
   It has been shown that miRNA genes frequently coincide with fragile sites and hot spots for chromosomal
   abnormalities or locate near cancer susceptibility loci that correlate with tumorigenesis.
   In addition, more than half of miRNAs
   reside in introns of their host genes and coexpress with their neighboring protein-coding sequences, and
   some may derive from common primary transcripts and even share the same promoters
5. typical features
6. regulated by
   1. impact of SNPG14
      that single nucleotide polymorphisms (SNPs), created
      by changes in DNA sequences of miRNA-coding genes
      or in an miRNA-binding site in mRNAs, are able to
      affect the biogenesis and function of miRNA.
      In the case of miR-146a, a common
      G/C polymorphism within the pre-miR-146a sequence
      decreased the generation of pre- and mature
      miR-146a and led to less efficient inhibition of target
      genes involved in the Toll-like receptor and cytokine
      signaling pathway, which contribute to the genetic
      predisposition to papillary thyroid carcinoma
   2. editing pathways of miRNAG14
      Approximately
      16% human pri-miRNAs are subject to A-to-I editing.
      the pri-miRNA
      transcripts of some miRNAs are subject to posttranscriptional
      modification by A-to-I RNA editing,
      which is catalyzed by the adenosine deaminases acting
      on RNA (ADARs
   3. methylation dependentG14
      The expression of
      miRNA genes, especially those locating near CpG islands,
      tends to be affected readily by methylation
      (63–65, 70) (Figure 2). Han and co-workers found
      that the expression of about 10% miRNAs tested
      are regulated by DNA methylation based on a comparative
      analysis on colon cancer cell line HCT 116
      with its derivative, a DNA methyltransferase 1 and
      3b double-knockout cell line.
      Two components of the p53 network,
      miR-34b and miR-34c, are also epigenetically silenced
      in colorectal cancer due to the hypermethylation of
      neighboring CpG islands
      
      1. picture (G14)
   4. circadian clock
      modulated mechanismG14
      miR-
      219 is targeted by the CLOCK and BMAL1 complex
      (74 ) and miR-132 is induced by photic entrainment
      cues through a MAPK/CREB-dependent mechanism
      to control clock-related gene expression and to reduce
      the entraining effects of light.
      miR-96 and miR-182 are reported to be involved
      in circadian rhythm regulation by modulating
      the expression of adenylyl cyclase VI in retina
7. still misteryG14
   We are yet to know the
   fates of these miRNAs, that is, after repressing their targets, what are the molecular mechanisms to get
   rid of these miRNAs?
8. functionG15
   Other experiments show that a
   single miRNA species may repress the production of hundreds of proteins, but that this repression often is relatively mild (much less than 2-fold).[44][45]
   
   The first human disease associated with deregulation of miRNAs was chronic lymphocytic leukemia. Other B cell
   malignancies followed
   Nine mechanisms of miRNA action are described and assembled in a unified
   mathematical model:[89]
   Cap-40S initiation inhibition;
   60S Ribosomal unit joining inhibition;
   Elongation inhibition;
   Ribosome drop-off (premature termination);
   Co-translational nascent protein degradation;
   Sequestration in P-bodies;
   mRNA decay (destabilisation);
   mRNA cleavage;
   Transcriptional inhibition through microRNA-mediated chromatin reorganization followed by gene silencing.
   
   1. mRNA silenced byG15
      As a result, these mRNA molecules are silenced, by one
      or more of the following processes:
      ※Cleavage of the mRNA strand into two pieces,
      ※Destabilization of the mRNA through shortening of its poly(A)tail, and
      ※Less efficient translation of the mRNA into proteins by ribosomes
9. animal and plant
   1. animalG15
      In contrast, animal miRNAs are able to recognize their target mRNAs by using as little as 6–8 nucleotides (the seed region) at the 5' end of the miRNA,[10][20][21] which is not enough pairing to induce cleavage of the target mRNAs
      
      Animal miRNAs are usually complementary to a site in the 3' UTR whereas plant miRNAs are usually complementary to coding regions of mRNAs. Unlike plant microRNAs, the animal microRNAs target diverse genes
   2. plantG15
      Plant miRNAs usually have near-perfect pairing with their mRNA targets, which induces gene repression through cleavage of the target
      transcripts.
      Instead of being cleaved by two different enzymes, once inside and once
      outside the nucleus, both cleavages of the plant miRNA are performed by a Dicer homolog, called
      Dicer-like1 (DL1)
      Animal miRNAs are usually complementary to a site in the 3' UTR whereas plant
      miRNAs are usually complementary to coding regions of mRNAs.
10. nomenclatureG15
    Under a standard nomenclature system, names are assigned to experimentally confirmed miRNAs before publication.[47][48]
    
    The prefix "miR" is followed by a dash and a number, the latter often indicating order of naming. For example, miR-124 was named and likely discovered prior to miR-456.
    
    A capitalized "miR-" refers to the mature form of the miRNA, while the uncapitalized "mir-" refers to the premiRNA and the pri-miRNA, and "MIR" refers to the gene that encodes them.[49]
    
    miRNAs with nearly identical sequences except for one or two nucleotides are annotated with an additional lower case letter. For example, miR-124a is closely related to miR-124b.
    
    Pre-miRNAs, pri-miRNAs and genes that lead to 100% identical mature miRNAs but that are located at different places in the genome are indicated with an additional dash-number suffix. For example, the pre-miRNAs hsa-mir-194-1 and hsa-mir-194-2 lead to an identical
    mature miRNA (hsa-miR-194) but are from genes located in different genome regions.
    
    Species of origin is designated with a three-letter prefix, e.g., hsa-miR-124 is a human (Homo sapiens) miRNA and oar-miR-124 is a sheep (Ovis aries) miRNA.
    
    Other common prefixes include 'v' for viral (miRNA encoded by a viral genome) and 'd' for Drosophila miRNA (a fruit fly commonly studied in genetic research).
    When two mature microRNAs originate from opposite arms of the same pre-miRNA and are found in roughly similar amounts, they are denoted with a -3p or -5p suffix. (In the past, this distinction was also made with 's' (sense) and 'as' (antisense)).
    
    However, the mature
    microRNA found from one arm of the hairpin is usually much more abundant than that found from the other arm,[2] in which case, an asterisk following the name indicates the mature species found at low levels from the opposite arm of a hairpin. For example, miR-124 and
    miR-124* share a pre-miRNA hairpin, but much more miR-124 is found in the cell.
11. biogenesisG15
    As many as 40% of miRNA genes may lie in the introns or even exons
    of other genes.
    The DNA template is not the final word on mature miRNA production:
    6% of human miRNAs show RNA editing (IsomiRs), the site-specific
    modification of RNA sequences to yield products different from those
    encoded by their DNA.
    
    1. picture (G15)
       Link: https://www.dropbox.com/s/z3cvs8zlpcszoce/miRNA%20biogenesis.png?dl=0
    2. step
       1. transcription
       2. nuclear processing
       3. nuclear export
       4. cytoplasmic processing
       5. RNA induced silencing complex
    3. link paper
       Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048316/
12. disease
    1. inherited disease
    2. cancer
    3. dna repair and cancer
    4. heart disease
    5. kidney disease
    6. nervous system
    7. obesity