Biologia molecolare applicata alle biotecnologie, Biologia molecolare, inglese

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IncRNA mRNA between!one!long!ncRNA!and!another!protein.!

!

miRNA sequestration miRNA-mediated repression This!means!that!complexes!of!protein!and!long!ncRNA!can!be!very!dynamically!regulated.!

Long!ncRNAs!are!very!huge!family!of!molecules!that!are!involved!in!several!aspect!of!the!cell!

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Figure 3 | lncRNAs influence mRNA processing and post-transcriptional regulation. a,b Long non-coding RNAs

(lncRNAs) can modulate mRNA processing. Splicing patterns can be influenced by lncRNAs that associate with the

Nature Reviews | Molecular Cell Biology

Geisler & Coller Nat Rev Mol Cell Biol 2013, 14:699 !

pre-mRNA (part a). For example, splicing of the first intron of neuroblastoma MYC mRNA is prevented by a natural

function.! antisense transcript . Antisense lncRNAs that associate with an mRNA could direct mRNA editing, perhaps through

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association of the duplex with ADAR (adenosine deaminase acting on RNA) enzymes that catalyse adenosine to inosine Patterns'and'mechanisms'…'

Many!different!classes!of!lncRNAs!are!able!to!work!in'the'cytoplasm:'

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conversion in double-stranded RNA (part b). c–f lncRNAs modulate post-transcriptional regulatory events. lncRNAs

63,66

containing SINEB2 repeat elements can upregulate translation through association with the 5ʹ region of an mRNA (part

68 One! characteristic! of! long! ncRNA! is! that! they' are' usually' poorly' expressed,! they! can! range!

S Interact!with!proteins!

c). lncRNAs containing Alu repeat elements associate with the Alu elements in the 3ʹ untranslated region (UTR) of an

mRNA, and this double-stranded structure can direct Staufen-mediated decay through a pathway that is molecularly between!well!expressed!or!very!poorly!expressed!(for!example!MALAT1!is!highly!expressed,!

S Regulate!the!postStranscriptional!maturation!of!other!proteins!

similar to nonsense-mediated decay (part d). lncRNAs can mask miRNA-binding sites on a target mRNA to block

70

miRNA-induced silencing through the RNA-induced silencing complex (RISC) (part e). Linear or circular lncRNAs can

72 while!HOTTIP!is!expressed!as!average!in!less!than!one!copy!per!cells!!).!!

S Work!as!scaffold!for!the!interaction!of!different!proteins;!

function as miRNA decoys to sequester miRNAs from their target mRNAs (part f).

74,75 The!number!of!copies!of!one!molecule!per!cell!is!not!a!clear!mean!of!the!function:!some!long!

Nuclear'functions:! Translation control. Uchl1AS mRNA stability control.

The mouse lncRNA pro- lncRNAs have also been impli-

Uchl1

duced from the (ubiquitin carboxyl-terminal cated in both positive and negative regulation of mRNA ncRNAs!are!expressed!in!few!copies!but!they!have!a!clear!function.!One!possible!explanation!

S RNA! editing! that! is! driven! by! the! work! of! a! ribonucleoprotein! complex! in! which! the!

esterase L1) locus was shown to upregulate translation of stability. For instance, Alu repeat-containing lncRNAs

Uchl1 mRNA through a repeat element . are involved in targeting mRNA transcripts for Staufen-

(FIG. 3c; TABLE 1) is! that! the! molecule! can! be' regulated' in' the' cell' cycle! so! it! is! present! only! in! one! specific!

protein! is! the! enzymatic! part! and! the! RNA! confer! the! specificity! of! action! of! this!

In this instance, sense and antisense transcripts are ori- mediated decay (SMD) . SMD is induced by Staufen 1

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ented in a 5ʹ head-to-head fashion such that the mature (STAU1) binding to a double-stranded structure in moment! of! the! cell! cycle.! ! Another! possible! explanation! is! that! HOTTIP! is! only! present! in! a!

protein! lncRNA contains a 73-nucleotide motif complementary mRNA 3ʹ UTRs. Through imperfect base pairing inter-

Uchl1

to the 5ʹ end of the mRNA. This sequence-specific actions with Alu elements in the 3ʹ UTR, Alu repeat- very!restricted!part!of!the!tissues,!in!particular!it!is!fundamental!during!development!of!legs!

S Control!of!the!splicing!

interaction serves to position the effector domain, which containing lncRNAs create STAU1-binding sites that

Uchl1AS trans-activate

is contained in the non-overlapping 3ʹ region of SMD and destabilize the target mRNA and!arms!and!there!is!a!clear!differential!expression!of!HOTTIP!that!is!mostly!present!in!the!

! and consists of a SINEB2 repeat element that upregu- .

(FIG. 3d; TABLE 1)

Uchl1 BACE1AS,

lates protein expression without changing mRNA By contrast, an antisense lncRNA that arises distal!compartments.!

Another!important!function!of!the!long!ncRNAs!is!the!possibility!to!compete'with'other'RNAs!

BACE1

levels. Bioinformatic analysis has identified 59 other from the (beta-site APP-cleaving enzyme 1) locus,

BACE1 BACE1AS

cDNAs with similar antisense orientations and SINEB2 increases stability of mRNA .

71 (TABLE 1) MALAT1!is!one!of!the!mostly'expressed!long!ncRNAs!but!it’s!function!is!redundant!because!its!

for!the!function!of!the!miRNAs:!one!miRNA!can!have!several!targets!and!the!same!target!may!

BACE1

elements, suggesting that this regulatory mechanism and mRNA form an RNA–RNA duplex, which

might be used at other loci . lncRNA-mediated transla- has been suggested to stabilize the mRNA by abrogation

68 KO!is!compatible!with!life,!so!the!number!of!copies!doesn’t!correlate!with!the!function.!

have!many!miRNA!acting!on!it.!When!we!have!two!different!RNA!(one!canonical!coding!RNA!

tional regulation has also been documented in yeast, in of miRNA-induced repression. More specifically, the

KCS1

which an antisense lncRNA was suggested to regu- antisense transcript and miR-485-5p compete for bind- In!general!the!number!of!long!ncRNA!is!lower!compared!to!genes,!and!they!can!interact!with!

and! one! non! canonical),! and! these! two! molecules! share! the! same! miRNA! target,! we! can!

BACE1

late translation of the inositol pyrophosphate synthase ing to the same region in the mRNA

71,72 (FIG. 3e;

KCS1 BACE1

mRNA expressed from the same locus. Through . mRNA encodes β-secretase, the rate-

TABLE 1) chromatin!in!a!different!way:!

influence!the!regulatory!function!of!one!miRNA,!for!example!increasing!the!concentration!of!

an unknown mechanism, which is thought to involve limiting enzyme in amyloid-β synthesis. Regulation of

BACE1

base pairing interactions between the antisense and expression, therefore, has important implications

the!long!ncRNA!we!can!compete!for!the!binding!of!miRNA!and!so!reducing!its!activity!on!the! Some!of!them!are!driven'by'the'proximity'of'interaction!→!Xist!is!able!to!bind!the!DNA!

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KCS1 BACE1AS

sense RNAs, expression of antisense RNA results in Alzheimer’s disease. Intriguingly, levels

in the production of truncated KCS1 protein . are increased in the brains of patients with Alzheimer’s

69 (TABLE 1)

canonical!mRNA.!! via! the! interaction! with! SAFFA! but! its! distribution! is! driven! by! the! initial! locus! of!

! expression;! it! is! express! in! 200S300! molecule! per! cells! by! on! locus! of! the! X! chr! and!

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NOVEMBER 2013 VOLUME 14

706 www.nature.com/reviews/molcellbio

! there!is!a!gradient!of!binding!of!Xist!with!the!neighboring!portion!of!its!chromosome!

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Long'ncRNA'as'scaffolds'that'integrate'diverse'regulatory'proteins' !

One! of! the! most! studied! functions! of! long! ncRNA! are! the! chromatinSlevel! function! and! the! MALAT1! is! expressed! at! very! high! level! but! it! is! present! into! the! chromatin! in! a!

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ability!to!work'as'a'hub'for'the'interaction'of'several'proteins.!The!idea!is!that!the!linker!RNA! specific! portion! of! the! chromatin! (called! nuclear! specle)! and! this! is! due! to! a! specific!

contains!domains!that!can!interact!with!several!proteins;!these!domains!are!joined!by!flexible! interaction!between!MALAT1!and!few!proteins!for!which!it!has!a!very!big!affinity,!so!

linkers!so!you!can!have!a!scaffold!molecule!that!can!recruit'different'molecules.! we!have!distinct!spots!of!distribution!of!MALAT1!into!the!chromatin.!The!spots!are!not!

We!can!have!different!types!of!interaction!between!protein!and!RNA;!they!can:! only!associated!with!the!chromosome!in!which!we!have!the!locus!for!MALAT1!but!it!is!

S Combine'different'proteins'creating'new'functions' able!to!move!around!the!nucleus!and!interact!with!different!locus.!!

S Co?localize'the'protein'with'the'DNA!→!opposite!to!the!canonical!function! !

S Allosteric'modulation!of!RNA!and!protein!! !

! 35! ! 36!

Eukaryotic'nuclei'exhibit'…' The! other! unique! aspect! is! that! many! long! ncRNAs! contain! these! tandems! of! repeated!

Nucleus!is!organized!in!different!compartments:! elements! (that! can! also! be! repeated! DNA! elements)! like! SINE,! LINE…! and! they! can! actually!

S Nucleolus! produce! RNA! molecules! that! can! interact! with! some! proteins! and! this! is! a! possible!

S Nuclear!bodies!! explanation!of!the!redundancy!of!these!RNAs!with!different!proteins.!!

Also! the! chromatin! is! organized! in! different! territories! and! chromosomes! are! usually! Another! property! of! long! ncRNAs! is! their! possibility! to! modulate' the' dynamic' assembly' and'

associated! with! a! specific! organization! also! when! they! are! not! condensed.! These! disassembly'the'state'of'one'territory.''

compartments! can! contain! active! or! inactive! genes! that! are! called! TAD! (Topologically! !

Associated! Domains):! loops! of! chromatin! that! are! usually! defined! by! the! presence! of! CTCF! Most'chromatin'associated'lincRNAs'act'through'epigenetic'mechanisms'

Most chromatin associated lincRNAs

boundary,! an! usually! all! the! elements! present! in! one! TAD! are! coSregulated! (so! one! or! more! This!possibility!of!interaction!has!lead!to!the!hypothesis!that!long!ncRNAs!have!a!role!in!the!

act through epigenetic mechanisms

enhancer!can!regulate!the!function!of!this!TAD).! regulation!of!the!epigenetic!machinery,!not!only!through!the!interaction!with!chromatin!but!

! also!with!the!other!elements!that!regulate!chromatin!structure!and!transcription.!

! They!seem!to!have!a!key!rule!in!differentiation.!

Long'ncRNAs'can'form'spatial'compartments'into'the'nucleus' Cis-tether (ie XIST) Trans regulation (ie HOTAIR)

Long!ncRNAs!can!also!play!a!recruitment!of!different!portion!of!the!chromosome!into!specific!

territories:!

!For! example! Firre! is! able! to! recruit! different! portion! of! different! chromosomes! into! a! very!

specific! place! characterized! by! an! active! transcription:! so! Firre! is! fundamental! for! the! !

translocation!of!portion!of!the!DNA!that!contain!the!enzymes!responsible!for!adipogenesis!in! ! &

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The EMBO Journal (2012) 31, 515–516 2012 European Molecular Biology Organization All Rights Reserved 0261-4189/12

Allosteric modification (i