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MicroRNA by Mind Map: MicroRNA

1. 0. Title

1.1. Overview of MicroRNA Biology

1.1.1. Link

1.2. miRNA-wikipedia

1.2.1. Link

2. 1. Definisi, existensi, fungsi

2.1. image

2.1.1. miRNA stem-loops

2.1.1.1. image2

2.2. Definisi

2.2.1. 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 .B2-[1][2][3]

2.2.1.1. 18-25

2.2.1.1.1. B3

2.2.1.1.2. 19-23 (B4, 1)

2.2.1.2. in bacteria

2.2.1.2.1. Whilst short RNA sequences (50 – hundreds of base pairs) of a broadly comparable function occur in bacteria, bacteria lack true microRNAs.B2[120]

2.3. function (in virus)

2.3.1. general

2.3.1.1. miRNa play key roles in the regulation almos every cellular process in all multicellular eukaryotes

2.3.1.1.1. B3-11

2.3.1.1.2. c13. including a role in the regulation of cellular differentiation, pro liferation and apoptosis (Hwang and Mendell, 2006).

2.3.1.1.3. C13. MiRNAs are recognized as key regulators of gene expression through the miRNA-guided RNA silencing pathway (Ambros, 2004; Bartel, 2004; He and Hannon, 2004 ),

2.3.2. virus

2.3.2.1. to host miRNA processing pathway to generate viral miRNA

2.3.2.1.1. B3

2.3.2.1.2. speculated that viral miRNA suprpress viral transcripst or host specific genes

2.3.2.1.3. increase their replication potiential, allow the evasion from innate immune system. virus can more easily and efficiently , help to promote a favorable cellular environment for viral replication and achivement of the life cycle

2.3.2.1.4. viral derived factors repress host miRNA cascade and are called RNA silencing supressor

2.3.2.1.5. the modulation of the machinery could be made by

2.3.2.2. C13. a key role in the regulation of replication and gene expression in viruses (Voinnet, 2005; Berkhout and Jeang, 2007). Jopling et al. (2005)

2.3.2.2.1. C13. many viruses can also encode miRNA, including the Epstein–Barr virus, the herpes sim plex virus and so on (Umbach et al., 2008; Pfeffer et al., 2004).

2.3.2.2.2. HBV

2.3.2.2.3. HIV

2.3.2.2.4. HCV

2.3.2.2.5. PFV-1

2.3.2.3. often assoc. with tumor progression

2.3.2.3.1. B3

2.4. existensi

2.4.1. miRNAs are abundant in many mammalian cell typesB2- [8][9]

2.4.1.1. appear to target about 60% of the genes of humans and other mammals B2- 10,11

2.4.1.2. family members

2.4.1.2.1. have similar sequence and secondary structure

2.4.1.2.2. Luc19. all encoded miRNAs that have high sequence homology, specifically identical nucleotides 2-8 from the 5′ end of the mature miRNA sequence (termed ‘extended seed’ [3]), are grouped into the same ‘miRNA family’ [14].

2.4.1.2.3. example

2.4.1.3. 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.b2 [67][68]

2.4.1.3.1. Sometimes

2.5. htm

2.5.1. devi

2.5.2. matematika

2.5.2.1. 60 % x 5000 = 3000

2.5.2.2. 5000 yen diambil oleh keluarga brazil

2.5.2.2.1. satu orang meninju badan temannya

2.5.2.3. lokasi dan waktu

2.5.2.3.1. Tenda daun -Liver

2.5.2.3.2. Badan tegap, tanda panah ke otak

2.5.2.3.3. Tidur terganggu -karena otot sakit

2.5.3. benih

2.5.3.1. 2-8

2.5.4. Menghancurkan benih

2.5.4.1. 5 hari

3. 2. History b2

3.1. 1993

3.1.1. 2 teams

3.1.1.1. Ambros, Lee, Feinbaum

3.1.1.1.1. first miRNA

3.1.1.2. Ruvkun's team

3.1.1.2.1. mode of action

3.1.2. lin4 miRNA inhibit Lin-14 protein (B2,-12)

3.1.2.1. in C. elegans larva developmental

3.1.3. nematode idiosyncracy

3.2. 2000

3.2.1. let-7 represses lin-41 (B2-13)

3.3. 2001

3.3.1. start to use the term " microRNA" to refer small regulatory RNA (B2-15,16,17)

3.4. first human disease related with miRNA

3.4.1. chronic lymphocytic leukemia

3.5. History

3.5.1. Luc19. In 1993, two groups led by Ambros and Ruvkun discovered lin-4, a small regulatory RNA that came to be known later on as the first microRNA (miRNA) ever identified [1, 2

3.6. htm

3.6.1. 93 = bagea

3.6.1.1. bagea, ambrose, di depan orang ruku

3.6.1.2. lina datang menaruh angka 4-14 di depannya. Tiba-tiba muncul cacing

3.6.2. 2000 = yurike

3.6.2.1. menyanyi Let i go

3.6.2.2. Lina jadi dancernya, bawa angka 41

3.6.3. 2001 = rehan

3.6.3.1. memberi nama pada anaknya

4. 3. Karakter

4.1. New Topic

4.1.1. Mechanism

4.1.1.1. biogenesis

4.1.1.1.1. miRNA mediated gene silencing

4.1.1.2. type complementary

4.1.1.2.1. canonical

4.1.1.2.2. non canonical

4.1.1.3. Model

4.2. 1. General target

4.2.1. 1. Plant

4.2.1.1. 1. Plant miRNAs usually have near-perfect pairing with their mRNA targets, which induces gene repression through cleavage of the target transcripts.[B2-19

4.2.2. 2. animal

4.2.2.1. 1. 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 (B2-10,35,36)

4.2.2.2. 2. Animal miRNAs are usually complementary to a site in the 3' UTR whereas plant miRNAs are usually complementary to coding regions of mRNAs.B2[85]

4.2.2.3. 3. Unlike plant microRNAs, the animal microRNAs target diverse genes.[B2-35

4.2.3. 3. not all out silencing

4.2.3.1. 1. only dampen and fine tube expression

4.2.3.2. 2. Generally, microRNAs do not act to completely silence their target expression7,8 genes, but rather decrease (b1-7,8)

4.2.3.3. 3. not on or off

4.3. 2. microRNA targets

4.3.1. 1. can target hundreds mRNA

4.3.1.1. 1. A given miRNA may have hundreds of different mRNA targets, and a given target might be regulated by multiple miRNAs.B2- [11][38]

4.3.1.2. 2. experiments show that a single miRNA species can reduce the stability of hundreds of unique messenger RNAs.[B2-40

4.3.1.2.1. 1. (much less than 2-fold).B2-[41][42]

4.3.1.2.2. Based on the complementarity with its target gene sequence, the mature miRNA induce either translational repression (partial complementarity) or mRNA degradation (perfect complementarity) [B4-7

4.3.1.3. 3. likened he function of siRNA

4.3.1.4. 4. similar to mRNA splicing

4.3.1.4.1. 1. (small nuclear RNAs) U1, U2, U4-6

4.3.1.4.2. 2. it is named snRNPs

4.3.1.5. 1. in 2 target

4.3.1.5.1. 1. mRNA

4.3.1.5.2. 2. non coding miRNA

4.4. 3. decreasing target expression

4.4.1. 2. The relative contribution of mRNA degradation and translational repression was tested using microarray and ribosome profiling assays and it was found that the majority of the microRNA effect was mediated through levels12 decreased target mRNA B1-12

4.4.1.1. activity

4.4.1.1.1. 3. (1) Cleavage of the mRNA strand into two pieces, (2) Destabilization of the mRNA through shortening of its poly(A) tail, and (3) Less efficient translation of the mRNA into proteins by riboso0mes (B2-4,5

4.4.1.1.2. 1. Nine mechanisms of miRNA action are described and assembled in a unified mathematical model:[B2-84] 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.

4.4.1.1.3. 1. induced decapping, induced deadenylation, altered cap protein binding, reduced ribosome occupancy, and sequestration of the mRNA from translational machinery are reported. (B1)

4.4.1.2. 1. For example, miR-373 has sequence complementarity to the promoter sequence of both E-cadherin and cold-shock domain-containing protein C2 (CSDC2). Transfection to increase levels of mature miR-373 caused increased mRNA expression of E II13. cadherin and CSDC2 by increased promoter occupancy by RNA Pol (B1-13)

4.4.2. 1. not all decreasing, Binding of RISC to the target mRNA has the potential to displace other repressive RNA binding proteins

4.4.2.1. 2. Increased expression of TNF- protein due to microRNA-mediated recruitment of RISC to the AU a rich element in the 3' untranslated region (3'UTR) of the TNF mRNA during cell cycle -a arrest was reported, suggesting that microRNAs can have stimulatory effects on expression mitosis14. depending on the timing within (B1-14)

4.4.2.2. 4. miR-466l increased the expression of the cytokine IL-10. The IL-10 mRNA, like many cytokine mRNAs, is targeted for degradation by proteins, such as tristetraprolin, that 'UTR16 bind the AU-rich elements (ARE) located in the IL-10 3'UTR (B1-16)

4.4.2.3. 3. Further, repression of the miR-122 target gene cationic amino acid transporter-1 (CAT1) was reversed in cells subjected to stress by amino treatment15 acid depletion, thapsigargin, or arsenite (B1-15)

4.4.3. the mature miRNA can increase the expression of the target gene under growth arrest condition [8 B4

4.5. 4. the ability of a single microRNA to have opposing functions in different systems

4.5.1. 1. One example is miR-125b in cancer, downregulated in multiple cancers such as hepatocellular, breast, and lung while overexpressed in colorectal, pancreatic, gastric, and leukemiasB1-23

4.5.1.1. 1. This discrepancy can be partially explained by the targets of miR-125b, like p53. In certain cancer tissues, overexpression of miR-125b results in a loss of p53, blocking apoptosis. In other tissues, p53 may be mutated and miR-125b loss will allow expression of oncogenic targets, like epidermal growth factor cancer23 receptor (EGFR) family members ERBB2/3 in breast (B1-23)

4.5.2. 2. Another study found the majority of microRNA targets in different cell types were not largely different, but were landscape24 more-so based upon differential 3'UTR isoforms and (B1-24)

4.6. 5. An additional concept in microRNA communication is how they interact together to target mRNAs. There are binding sites for many microRNAs in any given mRNA 3'UTR, allowing microRNAs to work together to increase repression of the target (b1)

4.6.1. 1. In the pancreas, miR-375, miR-124 and targeting let-7b were shown to work together to enhance myotrophin (B1-25)

4.7. htm

4.7.1. Binatang memakan tumbuhan. Tumbuhan jadi berkurang

4.7.2. target

4.7.2.1. 100

4.7.2.1.1. siRNA, miRNA splicing

4.7.2.1.2. also noncoding

4.7.2.1.3. cara hapal

4.7.2.2. seed

4.7.2.2.1. imperfect sequence

4.7.2.2.2. 2-8

4.7.2.2.3. degrees of complementary

4.7.3. slider, (menurun)

4.7.3.1. cara kerja

4.7.3.1.1. cleavage, destabilization, ribosom less efficiency

4.7.3.2. up

4.7.3.2.1. 373 -- Echaderin, CSDS2

4.7.3.2.2. miRNA med RISC -- TNF protein

4.7.3.2.3. 466-IL10

4.7.3.3. cara hapal

4.7.3.3.1. menggunting

4.7.3.3.2. naik

4.7.4. Menjadi dua orang, perempuan & laki-laki

4.7.4.1. 125 b

4.7.4.1.1. up

4.7.4.1.2. down

4.7.4.2. cara hapal

4.7.4.2.1. perempuan tindik mata

4.7.5. bekerja sama

4.8. Komponen

5. 6. degradation

5.1. microRNAs degrade much more easily than mRNAs, partly due to their length, but also because of ubiquitously present RNases. This makes it necessary to cool samples on ice and use RNase-free equipment.B2[121]

5.2. miRNA target fight back

5.2.1. Luc.19. miRNA pairing to specific non-canonical target sites with extensive complementarity to both 5′ and 3′ regions of the miRNA can reverse this outcome and target RNAs themselves can trigger degradation of bound miRNAs. This emerging miRNA destabilization mechanism is known as target RNA-directed miRNA degradation (TDMD)

5.3. The half-life of microRNAs is generally long and many can persist for 5 days or longer; however some microRNAs have turnover rapid (B1-29)

6. 5. Nomenclature B2

6.1. miR

6.1.1. miR

6.1.1.1. mature form

6.1.2. mir-

6.1.2.1. pre-miRNA and pri-miRNA

6.1.3. MIR

6.1.3.1. gene

6.2. a-1

6.2.1. additional lower case

6.2.1.1. nearly identical sequence

6.2.2. additional dash number suffix

6.2.2.1. 100% identical

6.3. p

6.3.1. 3p or 5p

6.3.1.1. roughly similar amount

6.3.2. *

6.3.2.1. low amount

6.4. 3 letter prefix

6.4.1. species of origin

6.5. htm

6.5.1. miRa1 jadi p3

6.6. Nomenclature

6.6.1. Luc19. miRNAs are named using the ‘miR’ prefix followed by a dash and a unique identifying number (e.g. miR-17, miR-93). Exceptions to the naming convention are miRNAs found in early genetic studies

6.6.2. Luc19. three-letter prefix preceding the miRNA name defines the organism

6.6.3. Luc19. Paralog miRNAs are indicated with lettered suffixes (a, b, c, etc.) distinguishing miRNAs with nearly identical mature sequences

6.6.4. Luc19. If the same mature miRNA is generated from multiple loci, numeric suffixes (-1, -2, -3, etc.) are added at the end of the miRNA name (e.g., let-7a-1, let-7a-2 and let-7a-3)

6.6.5. Luc19. the mature miRNA strands are named with the suffixes ‘-5p’ and ‘-3p’.

7. 7. Biogenesis

7.1. animal

7.1.1. transcription

7.1.1.1. RNA pol II (B2-48,49)

7.1.1.1.1. polymerase often binds to a promoter found near the DNA sequence, encoding what will become the hairpin loop of the pre-miRNA. The resulting transcript is capped with a specially modified nucleotide at the 5' end, polyadenylated with multiple adenosines (a poly(A) tail),b2[48][44] and spliced.

7.1.1.1.2. one arm of an ∼80 nucleotide RNA stem-loop that in turn forms part of a several hundred nucleotide-long miRNA precursor termed a primary miRNA (pri-miRNA).b2.[48][44]

7.1.1.2. RNA POL III

7.1.1.2.1. RNA polymerase III (Pol III) transcribes some miRNAs, especially those with upstream Alu sequences, transfer RNAs (tRNAs), and mammalian wide interspersed repeat (MWIR) promoter units.b2.[50]

7.1.1.3. 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. B2-2

7.1.1.4. As many as 40% of miRNA genes may lie in the introns or even exons of other genes.B2-[43] These are usually, though not exclusively, found in a sense orientation,B2-[44][45] and thus usually are regulated together with their host genes.B2- [43][46][47]

7.1.2. nuclear processing

7.1.2.1. A single pri-miRNA may contain from one to six miRNA precursors. These hairpin loop structures are composed of about 70 nucleotides each. Each hairpin is flanked by sequences necessary for efficient processing.

7.1.2.2. The double-stranded RNA (dsRNA) structure of the hairpins in a pri-miRNA is recognized by a nuclear protein known as DiGeorge Syndrome Critical Region 8 (DGCR8 or "Pasha" in invertebrates), named for its association with DiGeorge Syndrome. DGCR8 associates with the enzyme Drosha, a protein that cuts RNA, to form the Microprocessor complex.[b2 51][52] In this complex, DGCR8 orients the catalytic RNase III domain of Drosha to liberate hairpins from pri-miRNAs by cleaving RNA about eleven nucleotides from the hairpin base (one helical dsRNA turn into the stem).[53][54] The product resulting has a two-nucleotide overhang at its 3' end; it has 3' hydroxyl and 5' phosphate groups. It is often termed as a pre-miRNA (precursor-miRNA). Sequence motifs downstream of the pre-miRNA that are important for efficient processing have been identified.b2[55][56][57]

7.1.2.2.1. Luc.19. These are processed to mature miRNAs through successive endonucleolytic cleavages by two RNase III-type enzymes [33]. The first cleavage is carried out by the nuclear protein complex called microprocessor, comprising the RNase III enzyme Drosha [34] and the double-stranded RNA-binding protein DiGeorge syndrome critical region 8 (DGCR8) [35, 36]. The cleavage of the pri-miRNA releases the pre-miRNA, a structured ‘hairpin-like’ precursor transcript of ~70 nucleotides [17-19] with a 5′ phosphate and a characteristic 2-nucleotide 3′ overhang, typical of cleavage products by RNase III-type enzymes [33].

7.1.2.3. Pre-miRNAs that are spliced directly out of introns, bypassing the Microprocessor complex, are known as "Mirtrons." Originally thought to exist only in Drosophila and C. elegans, mirtrons have now been found in MAMMALS b2-58

7.1.2.4. As many as 16% of pre-miRNAs may be altered through nuclear RNA Most commonly, enzymes known as adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine (A to I) transitions. RNA editing can halt nuclear processing (for example, of pri-miR-142, leading to degradation by the ribonuclease Tudor-SN) and alter downstream processes including cytoplasmic miRNA processing and target specificity (e.g., by changing the seed region of miR-376 in the central nervous system).b2[59]

7.1.3. nuclear export

7.1.3.1. This protein, (EXPORTIN 5) a member of the karyopherin family, recognizes a two-nucleotide overhang left by the RNase III enzyme Drosha at the 3' end of the pre-miRNA hairpin. Exportin-5-mediated transport to the cytoplasm is energy-dependent, using GTP bound to the Ran protein.b2 [62]

7.1.3.1.1. Luc.19, The export receptor Exportin 5 (XPO5) facilitates the transport of pre-miRNAs from the nucleus to the cytoplasm [37-39]. As shown in a recent XPO5 knockout study, its role in the miRNA maturation process is not essential and can be complemented by alternative mechanisms [40].

7.1.4. cytoplasmic processing

7.1.4.1. In the cytoplasm, the pre-miRNA hairpin is cleaved by the RNase III enzyme Dicer.b2[63] This endoribonuclease interacts with 5' and 3' ends of the hairpin[64] and cuts away the loop joining the 3' and 5' arms, yielding an imperfect miRNA:miRNA* duplex about 22 nucleotides in length.b2[63] Overall hairpin length and loop size influence the efficiency of Dicer processing. The imperfect nature of the miRNA:miRNA* pairing also affects cleavage.b2[63][65] Some of the G-rich pre-miRNAs can potentially adopt the G-quadruplex structure as an alternative to the canonical stem-loop structure. For example, human pre-miRNA 92b adopts a G-quadruplex structure which is resistant to the Dicer mediated cleavage in the cytoplasm.b2[66]

7.1.4.1.1. Luc.19, Once in the cytoplasm, a second RNase III enzyme Dicer further processes the precursor hairpin and releases the mature miRNA duplex embedded in the stem of the pre-miRNA [41, 42]. Dicer acts as a ‘molecular ruler’ [43, 44] and yields specifically 21-23 nucleotides long mature miRNA duplex with a 5′ phosphate and 2-nucleotide 3′ overhangs on each end [45]. In vertebrates, the ‘dicing’ process is supported and modulated by two Dicer-binding proteins: trans- activation response (TAR) RNA-binding protein (TRBP) and protein activator of the interferon-induced protein kinase (PACT) [46-48]. Dicer has a fundamental role in the miRNA biogenesis, although its depletion in a recent knockout study didn’t abolish completely the expression of many canonical miRNAs [40], suggesting the existence of alternative pathways for miRNA maturation [21, 40].

7.1.5. image

7.1.5.1. biogenesis

7.1.5.1.1. image

7.2. tumbuhan

7.2.1. miRNA biogenesis in plants differs from animal biogenesis mainly in the steps of nuclear processing and export. 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). DL1 is expressed only in the nucleus of plant cells, which indicates that both reactions take place inside the nucleus. Before plant miRNA:miRNA* duplexes are transported out of the nucleus, its 3' overhangs are methylated by a RNA methyltransferaseprotein called Hua-Enhancer1 (HEN1). The duplex is then transported out of the nucleus to the cytoplasm by a protein called Hasty (HST), an Exportin 5 homolog, where they disassemble and the mature miRNA is incorporated into the RISC.B2[69]

7.3. htm

7.3.1. Sensor

7.3.1.1. oleh Rina Hasyim disensor ke polisi

7.3.1.2. Polisi memberi ikat rambut ke rina hasim

7.3.2. Dagu Rosa + pasha

7.3.2.1. digunting

7.3.2.2. digantung agar berbentuk angka 16

7.3.3. export

7.3.3.1. karyo pakai tenaga

7.3.4. dice menjadi double

7.3.4.1. tiba2 punya gigi

7.3.5. pohon tomat berbuah dice

7.3.5.1. dice dicat dengan hena

7.3.5.2. dikasih ke asty

8. 8. RNA induced silencing complex

8.1. Luc.19 The miRNA strand loaded into AGO guides RISC to complementary target sites usually located in the 3′ untranslated region (3′ UTR) of target mRNAs [14]. More than 60% of protein-coding genes contain at least one conserved miRNA-binding site and are predicted to be regulated by miRNAs [59]. In

8.1.1. mechanism of mirna function

8.2. strand selection

8.2.1. Luc.19 The miRNA-mediated gene silencing is the result of a remarkable interplay between a miRNA and an effector protein of the Argonaute (AGO) family that form the RNA-induced silencing complex (RISC, also called miRISC) [49]. After cleaving the pre-miRNA (Figure 5), Dicer and its helper protein TRBP or PACT transfer the mature miRNA duplex to an AGO protein forming the RISC loading complex (RLC) which leads to RISC maturation [22, 23]. Interestingly, AGO proteins can be loaded with essentially any mature miRNA sequence, which makes the RISC fully versatile and capable of targeting and silencing effectively any (partially) complementary target [50-53]. However, the mature miRNA duplex generated by Dicer cleavage contains necessarily two miRNA strands [33] (Figure 5). Generally, only one of the miRNA strands (the ‘guide’ strand) is selected and retained in AGO, while the other strand (the ‘passenger’ strand; also known as miRNA*) is discarded [22, 23]. The released passenger strand is rapidly degraded, resulting in a prominent bias in the cellular miRNA pool towards the guide strand [20]. Once loaded into AGO, the guide strands are stably retained, preventing rapid turnover and extending their lifetime on the order of several days [54, 55]. Therefore, the selection of one or the other strand as guide for RISC is not random and of crucial importance for the downstream target repression [23]. The fate of the two strands is influenced by the identity of their 5′ terminal nucleotides and the relative thermodynamic stability of the two ends of the miRNA duplex [56-58]. In fact, the duplex asymmetry is recognized by the RLC and the loading preference is given to the strand with thermodynamically less stable 5′ end [56, 57] and preferably a 5′ terminal adenosine or uridine [58]. The AGO protein loaded with a single-stranded miRNA dissociates from Dicer/TRBP and forms the mature RISC (also called miRISC) [22, 23] (Figure 5). The hallmark of RISC is the use of the sequence information encoded in the guide strand to direct the gene silencing machinery to complementary target transcripts (Figure 6)

8.2.2. Luc.19 only one of the produced miRNA strands (called ‘guide’ strand) is usually biologically active and much more abundant in the cell than the other strand which is considered to be inactive and therefore named ‘passenger’ strand (also known as ‘miRNA*’, pronounced ‘miRNA star’) [21-23].

8.3. structure

8.3.1. Argounate

8.3.1.1. are central to RISC function. Argonautes are needed for miRNA-induced silencing

8.3.1.2. structure

8.3.1.2.1. and contain two conserved RNA binding domains: a PAZ domain that can bind the single stranded 3' end of the mature miRNA and a PIWI domain that structurally resembles ribonuclease-H and functions to interact with the 5' end of the guide strand.

8.3.1.3. character

8.3.1.3.1. Some argonautes, for example human Ago2, cleave target transcripts directly; argonautes may also recruit additional proteins to achieve translational repression.B2[77]

8.3.1.4. family

8.3.1.4.1. AGO (with four members present in all mammalian cells and called E1F2C/hAgo in humans), and PIWI (found in the germ line and hematopoietic stem cells).B2[71][77]

8.3.2. Additional RISC components include TRBP [human immunodeficiency virus (HIV) transactivating response RNA (TAR) binding protein],B2[78] PACT (protein activator of the interferon-induced protein kinase), the SMN complex, fragile X mental retardation protein (FMRP), Tudor staphylococcal nuclease-domain-containing protein (Tudor-SN), the putative DNA helicase MOV10, and the RNA recognition motif containing protein TNRC6B. B2[62][79][80]

8.4. 2 types

8.4.1. Argonaute-catalyzed slicing mechanism

8.4.1.1. Luc19. In mammals, the slicing activity is catalyzed by Argonaute2 (AGO2) which cleaves the phosphodiester bond linking target nucleotides paired to positions 10 and 11 from the 5′ end of the guide miRNA leaving a 3′ hydroxyl and 5′ phosphate [50, 52, 62-64]. The other Argonaute paralogs (AGO1, AGO3 and AGO4) have been thought to serve as slicer- independent effector proteins of the RISC, silencing gene expression through translational inhibition and deadenylation but not cleavage [60].

8.4.1.2. Luc.19 The AGO-catalyzed slicing mechanism is common in plants [66]

8.4.1.2.1. Luc19. very few examples of AGO-catalyzed slicing have been reported in mammals [63, 67, 68].

8.4.2. Slicing-independent translational repression and mRNA decay The

8.4.2.1. Luc19. Key component among the recruited silencing factors are GW182 proteins, present as three paralogs in mammals, TNRC6A/B/C [78-80]. Guided by the miRNA, AGO associates with the target mRNA and recruits TNRC6 which acts as a structural scaffold responsible for the assembly process of the whole silencing machinery [60]. TNRC6 interacts with the poly(A)-binding protein (PABPC) associated with the poly(A) tail of the mRNA and recruits cytoplasmic deadenylase complexes PAN2-PAN3 [81, 82] and CCR4-NOT [83-85], either of which shortens the poly(A) tail of the mRNA and induces 3′ 5′ mRNA decay. A short or absent poly(A) tail leads to mRNA decapping with the removal of the 7-methylguanylate (m7G) cap by DCP1-DCP2 decapping enzymes [81]. The unprotected 5′ end is susceptible to 5′-3′ mRNA degradation [86]. Simultaneously, CCR4- NOT recruits DDX6, a helicase that activates the decapping complex and inhibits the translation of the mRNA [87, 88]. Although the translational repression occurs rapidly, its effect on the steady-state silencing of endogenous mRNAs is relatively weak because target mRNAs remain stable. Only at a later stage, the shortening of poly(A) tails induces irreversibly their degradation [75, 89, 90]. In fact, in diverse cell types and conditions mRNA decay is by far the dominant miRNA-mediated silencing mechanism and is generally responsible for 66-90% of target repression [61, 91]. The initial translational repression without irreversible mRNA decay can be rescued and allows flexibility in the miRNA- mediated silencing mechanism that can either switch off or fine-tune protein expression [92]

8.5. other

8.5.1. RISC is also known as a microRNA ribonucleoprotein complex (miRNP);B2[71] A RISC with incorporated miRNA is sometimes referred to as a "miRISC."

8.5.2. Generally, only one strand is incorporated into the miRISC, selected on the basis of its thermodynamic instability and weaker base-pairing on the 5' end relative to the other strand.B2[72][73][74] The position of the stem-loop may also influence strand choice.[75] The other strand, called the passenger strand due to its lower levels in the steady state, is denoted with an asterisk (*) and is normally degraded. In some cases, both strands of the duplex are viable and become functional miRNA that target different mRNA populations B2[76]

8.6. , it has been recently reported that miRNA can also act in a RISC-independent manner on the transcriptional level by interaction with ribonucleoprotein or direct binding to DNA [9,10,11].B4

8.7. htm

8.7.1. RISka

8.7.1.1. MIRIN

8.7.2. Family Pacar Argo Tari Saman

8.7.2.1. Petani tidur di Bioskop

8.7.3. Argo

8.7.3.1. Wiwi pilih PAS

8.8. proses independent slicing

8.8.1. gambar

9. 9. regulation of microRNAs

9.1. MicroRNAs are regulated by mechanisms similar to other RNAs, (B1-26)

9.1.1. Intronic microRNAs are often regulated by their host gene, and processed from the intron, but may have a distinct promoter region

9.1.2. Intergenic microRNAs typically have independent promoter elements.

9.2. This shows us that microRNAs can indirectly regulate their transcription.

9.2.1. MiR-200c is involved in the epithelial-to-mesenchymal transition and is transcriptionally repressed by zinc finger E-box-binding homeobox 1 27. (ZEB1) However, if miR-200c is overexpressed it targets ZEB1 allowing for transcription, creating a forward-feedback loop (B1-27)

9.3. htm

9.3.1. similar to RNA

9.3.2. intronic-intergenic

9.3.3. regulate their self

9.3.3.1. 200-ZEB

9.3.4. Komputer Internet

9.3.4.1. 200 ZEB

10. 10. affect the function

10.1. mRNA

10.1.1. Similar to the inclusion or exclusion of microRNA binding sites through alternative polyadenylation, alternative splicing has the potential to alter both the coding and UTR sequences of target mRNAs and thus alternative splicing has the potential to change microRNA binding potential. While alternative splicing is understood to alter the coding region of an mRNA, alternative usage of splice sites at the 3' end of the transcript can result in completely different 3'UTR sequences for otherwise related mRNAs

10.1.1.1. alternative cleavage

10.1.2. Alternative splicing of this contains64. lncRNA has a direct effect on expression of the microRNAs it Alternative polyadenylation or alternative splicing can both change the conversation by affecting the responsiveness of the target gene to microRNA binding (presence or absence of the binding site) or by changing the level of the microRNA itself (i.e., miR-21 and miR-412).

10.1.2.1. Poly adenylation signal

10.1.2.1.1. The PAS generally consists of a hexanucleotide 5'AAUAAA, but single base variants are described

10.1.2.1.2. alternative polyadenylation can result in the loss or gain of support microRNA binding sites, a concept with experimental (B1-57,59)

10.2. miRNA

10.2.1. modified (isomiR)

10.2.1.1. Modifications of the 3' end of mRNAs alter the stability of the RNA, primarily by degradation46 allowing for the decapping of the 5' end followed by exonuclease degradation (B1-46)

10.2.1.2. type of modification

10.2.1.2.1. urydilation

10.2.1.2.2. adenosine deamination to inosine

10.2.1.2.3. 3' nucleotide additions

10.2.1.2.4. 5' end microRNA

10.3. SNP

10.3.1. SNP (present in ~1–5% of individuals).

10.3.2. a number of SNPs do change the function of their host gene; some also alter microRNA function or expression

10.3.3. example

10.3.3.1. An example of a disease-related SNP that regulates microRNA function by altering a microRNA binding site was found in the 3'UTR of KRAS. The allele resides in a binding site for let-7, and cells harboring a KRAS allele with the variant expressed higher levels of KRAS. Importantly, the variant was found in 18–20% of patients with non-small cell lung population65 cancer, but only 6% of the general (b1,65)

10.4. htm

10.4.1. miRNA marah ambil senapan

10.4.1.1. Urin adam 35 liter

10.4.1.1.1. linda lapan lewat jendela

10.4.1.1.2. ADAM -151 (TOMAT)

10.4.1.1.3. TIGA-122 (tENDA DAUN)

10.4.1.1.4. LIMA - Topan Danau

10.4.1.2. membelah, polisi

10.4.1.3. senapan sangat keras dipakai

11. 11. clinic application

11.1. For example, miR16 contains a sequence complementary to the AU-rich element found in the 3'UTR of many unstable mRNAs, such as TNF alpha or GM-CSF.[81]

11.2. prognosis

11.2.1. MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells. Another role for miRNA in cancers is to use their expression level for prognosis. In NSCLC samples, low miR-324a levels may serve as an indicator of poor survival.B1[B2144] Either high miR-185 or low miR-133b levels may correlate with metastasis and poor survival in colorectal cancer.B1[B2145]

11.2.2. In classical Hodgkin lymphoma, plasma miR-21, miR-494, and miR-1973 are promising disease response biomarkers.[B2148]

11.3. treatment

11.3.1. MicroRNAs have the potential to be used as tools or targets for treatment of different cancers.B2[149] The specific microRNA, miR-506 has been found to work as a tumor antagonist in several studies. A significant number of cervical cancer samples were found to have downregulated expression of miR-506. Additionally, miR-506 works to promote apoptosis of cervical cancer cells, through its direct target hedgehog pathway transcription factor, Gli3.B2[150][151]

11.4. diagnostic

11.4.1. Bile from cholangiocarcinoma and control patients was assayed for the presence of microRNAs. They discovered a 5-microRNA panel that predicted early tumors better than carbohydrate antigen (CA19-9), with an overall sensitivity of 67% and specificity of 96%. Combining the microRNA panel with CA19-9, sensitivity increased to 89.7%. B1-32)

11.4.2. Teori

11.4.2.1. differ betwwen disease and normal tissue

11.4.2.2. microRNA are secreted by cells through exosomes. extracelluler vesicles (B1-30)

11.4.2.2.1. stable in bodily fluides (B1-31)

11.4.2.3. MicroRNAs have been isolated from blood (serum and plasma), saliva, urine, feces, follicular fluid, synovial fluid, pancreatic juice, bile, gastric juice, and other bodily fluids, and are being examined for utility as biomarkers for related diseases

11.4.2.4. Many other miRNAs also have links with cancer and accordingly are sometimes referred to as "oncomirs"

11.5. disease

11.5.1. inherited disease

11.5.1.1. A mutation in the seed region of miR-96, causes hereditary progressive hearing loss.B2[141] A mutation in the seed region of miR-184, causes hereditary keratoconus with anterior polar cataract. B2[142] Deletion of the miR-17~92 cluster, causes skeletal and growth defects.B2[143]

11.5.1.1.1. miR-17--92)

11.5.2. mir 122

11.5.2.1. MiR-122 plays a role in infection34 cholesterol metabolism, hepatocellular carcinoma and hepatitis C virus (B1-34)

11.5.2.1.1. B3- Girard 2008)

11.5.2.2. high level in normal hepatocytes (70% of total miRNA population)

11.5.2.2.1. Lagos quintana, B3, 2002

11.5.3. miR-21

11.5.3.1. in majority of cancer

11.5.3.2. caspace activation (B1-37-38)

11.5.3.3. Hepatocellular carcinoma cell proliferation may arise from miR-21 interaction with MAP2K3, a tumor repressor gene.[147]

11.5.4. miR-14

11.5.4.1. targeting Hedgehog in Drosophila cells

11.5.5. miR-150

11.5.5.1. conferring functional targeting of c-Myb (B1-42)

11.6. htm

11.6.1. disease

11.6.1.1. Berdiri di atas band sambil melihat google map di telpon

11.6.1.1.1. BAN- Telinga

11.6.1.1.2. Map - Duta

11.6.1.1.3. Telpon - Katarak

11.6.1.2. melihat Thomas jorgie meninju liver

11.6.1.2.1. tomas - makan bakso

11.6.1.2.2. tinju - tulang

11.6.1.2.3. liver -tdd

11.6.2. Prognosis

11.6.2.1. Halo, menelpon ke RS karena sakit di paru dan rektum

11.6.2.1.1. Halo - duta pbb, tembak jagung

11.6.2.1.2. Paru -GDP

11.6.2.1.3. rektum

11.6.3. pengobatan

11.6.3.1. Joker di RS pegang mesin kasir

11.7. eukaryotic cells

11.7.1. important in the development and function of immune system

11.7.1.1. B3-Baltimore 2008

11.8. Example of mirna

11.8.1. Luc19. oncogenic miR-17 [8, 9] and tumor-suppressive let-7 [10, 11].

11.8.2. Luc19. Dysregulation of miRNA expression and function has been found in many human diseases [131], especially in the context of cancer [132] where some miRNAs can act as tumor suppressors [10], whereas oncogenic miRNAs (called ‘oncomirs’) are functionally associated with the promotion of cancer [133]. S

11.9. HBV

11.9.1. Role of miRNA in

11.9.1.1. HBV Replication

11.9.1.1.1. miR-122

11.9.1.1.2. miR-1

11.9.1.1.3. miR-372/373

11.9.1.1.4. let-7

11.9.1.1.5. miR-501

11.9.1.2. Immune Evasion

11.9.1.2.1. miR 155

11.9.1.2.2. miR 181a

11.9.1.2.3. miR 146

11.9.1.3. HBV Chronic infection

11.9.1.3.1. MIr 152

11.9.1.3.2. MIR- 122

11.9.1.3.3. mir-125a

11.9.1.3.4. miR-199a-3p

11.9.1.4. HBV related cirrochis

11.9.1.4.1. the global miRNA expression profile analysis of human liver tissues from different inflammation, infection and cancer states are not always consistent. It sometimes revealed a particular profile due to the association of both viral hepatitis and cirrhosis [60] or regarding to the type of viral hepatitis [22] and sometimes showed no difference [61].

11.9.1.4.2. miR-29

11.9.1.5. HBV related HCC

11.9.1.5.1. miR-17-92

11.9.1.5.2. miR-155

11.9.1.5.3. miR-122

11.9.2. general role

11.9.2.1. B4. They reflect the cellular pathways that are altered as a result of the viral infection, viral infection that triggers the liver cirrhosis and carcinogenesis as side effects. On the viral point of view, the dysregulated pathways mirror the strategies of the virus to allow its replication and evade the host defense mechanisms to survive. On the cellular point of view, they mirror the immune response that tries to get rid of the intruder and that becomes dysregulated

12. 12. Research

12.1. Database

12.1.1. Luc.19 The latest release of the miRNA database ‘miRBase’ (http://www.mirbase.org) lists 1’917 miRNA gene annotations in human [7].

12.1.1.1. Luc.19 The latest release of the database (v22, March 2018) contains 38’589 miRNA loci from 271 species, expressing 48’885 mature miRNAs.

12.1.1.2. Across all species, in excess of 5000 different miRNAs had been identified by March 2010.[119]

12.1.1.3. Luc. 19 658 confidently annotated miRNAs have been identified in human, 614 in mouse (Mus musculus), 155 in fly (Drosophila melanogaster) and 81 in worm (Caenorhabditis elegans) (Table S1-4). The most evolutionarily conserved of these can be grouped into 89 miRNA families comprising 200 miRNA genes [3]

12.1.1.4. Luc.19 However, not all the sequences annotated in miRBase have been experimentally validated. In this respect, curated databases like DIANA-TarBase (http://www.microrna.gr/tarbase) index only experimentally supported miRNAs [29] (Figure 4).

13. htm

13.1. DEVI & SOEKARNO berKARATE dengan Om NOM, DOG menonton sambil baca buku REGULASI & BIOLOGI, di dekatnya ada KLINIK yang terbakar oleh API besar