

ubiquitin ligase ligase ennariyappedunna ubiquitin ligase ligase (manushyan/mouse), "yubi 3eiii" locusil "elenkaattu" (valia noonn-coding antisense traanskript) enna valia traanscriptinte bhaagamaayi traanskript cheytha antisense dna straandinte peraanu. yubi 3 eiii" locus mudranam cheyyappedukayum kendra naadeevyavasthayil maathru alleelil ninnu maathram prakadippikkukayum cheiyunnu. achadicha lokkiyil noonn-coding antisense traanscriptukal palappozhum kaanappedunnathinal, "elenkaattu" ennathinte ghattangalil bhaagathiloodeyaanu pithru alleelile maathru nishabdamaakkunnathu ennu karuthappedunnu. maathru chromosomil "yubi 3 eiii" illaathaakkunnathum koodaathe/allengil mutation aanjalmaan syndrome (aas) undaakkukayum "yubi 3 eiii-aatts" eee rogathinu oru therapy kandethunnathile oru pradhana vashamaanenn theliyikkukayum cheyyum. maathru maathru alleel ulla rogikalil nishkriyamaanenkilum, pithru alleel kedukoodaathe pakshe epijenattikkalaayi nishabdamaanu. nishabdamaakkiyittillengil, rogikalenna nilayil pithaavinte alleel sajeevamaaya yubi 3 eiii proteente uravidamaakaam. athinaal, pithaavinte "yubi 3 eiii" nishabdamaakkunnathil "yubi 3 eiii-aatts" engane ulppettekkaam ennathinte samvidaanangal manasilaakkunnath puthiya chikilsakalilekku nayichekkaam. bhaviye ennathinte transcription kurachukondu, elikalkku nalkunna toppottekkan enna marunnu pithaavinte pithaavinte jeeninte sajeevamaaya aavishkaaram kaanikkunna sameepakaala padanamaanu eee saadhyatha theliyikkunnathu.
"elenkaattu" samghadana.
manushyante neuronukalilo" pradhaanamaayum kendra naadeevyavasthayile (cns) pithrthva alleelil ninnu "elenkaattu" ennathinte bhaagamaayi prakadippikkunnu. ekadesham 450 keey. bii. ezz neelamulla traanskript yuu-exonukalil ninnu aarambhich ethir strandle "yubi 3 eiii" vare vyaapikkunnu, orupakshe athinappurathekku. snoorf/ezz. enn. aarr. pii. enn" ennathinte promoter mudranam cheiyunna kendravum yuu-exon mekhalayilaanu kaanappedunnath. eee pradesham illaathaakkunnathu illaathaakkunnathu transcription nirthalaakkunnathinaal promoter mekhala anivaaryamaan. promoterinu sameepam pdablues-aisi undu, pdablues-aisiyude mukalilaayi ekadesham 35 kbs aas-aisi aanu. eee rund pradeshangalum muzhuvan "elenkaattu" izhayudeyum aavishkaarathe niyanthrikkumenn karuthappedunnu. promoteril ninnu aarambhich, muzhuvan traanscriptum traanskript cheyyaanum transcriptionushesham kooduthal prosess cheyyaanum splies cheyyaanum kazhiyum. neurosi trendukal" ennathil avalokanam cheythu.
yuu-exon promoter mekhalaykku aduthaayi sthithi cheiyunna "snrpn/snoorf" aanu, ithu manushyaril "snrpn" allengil "snoorf" aayi vibhajikkaam (elikalil ithu oru bistronic traanscriptaayi thudarunnu). "kosha nucleusilekku praadeshikavalkkarikkuppadu anjjaathamaaya pravartthanatthinte oru proteinulla "snrpn" kodukal. "oru cheria nuclear raibo nucleoproteinulla "snoorf" kodukal. eee proteinukalil bhooribhaagavum spliesingil earppettirikkumbol, eee prathyeka proteente punk ithuvare arivayittilla. ezz. enn. aarr. pii. enn/snoorf" ennathil ninnu thaazhekku, athinte intronukalkkullil niravadhi sii/dii boxes snoornakalude sequenceukal undu. mikka sii/dii boxes snornakalum marnah methylationil pravartthikkunnu. ennirunnaalum, aduthide, neuronukalilo" enna snord 115-leeii oru snorna, serotonin risapttar risapttar pree-marnayude badal spliesingine mattunnathaayi kandethi. koodaathe, eee snornaykku anchu vyathyastha marnakalude spliesing mattaanulla kazhivundu. snornakalude shrenikalil onnaanu nested ipdablue (impint cheytha preder-villi), ithu oru noonn-coding mekhalayaanu, athinte illaathaakkal preder-villi syndromine kaaranamaakumenn karuthappedunnu.
model samvidaanangal.
eliyum manushyanaaya manushyanaaya yum orthologas aanu, koodaathe pradeshangalude pothuvaaya oorganaiseshanukal samaanamaan. udaaharanathinu, mouse locusil "snoorf/snrpn", snornas, ipdablue ennivayum adangiyirikkunnu. bhaviye traanskripttukalude sthaanangalum neelavumaanu pradhana vyathyaasangal. manushyante manushyante chromosome 15-lum mouse maathaavinte chromosome 7-lum sthithicheyyunnu. pithaavinte ulppedeyulla "elenkaattu" enna mousinu ekadesham 1000 kebi neelamundu, manushyante 450 kebi "elenkaattu" nekkaal valare neelamundu. eliyudeyum manushyarudeyum "lncat/ube3a-ats"-nte samanamaaya oorganaiseshanum mouse "ube3a" locus achadichirikkunnathil, mudranam padikkunnathinum "ube3a/ube3a-ats" thammilulla edapedalukal padikkunnathinum mouse oru mikacha model samvidaanamaanu. koodaathe, mouse neuronukal avayude achadi reethi samskaarathil nilanirthunnathu thudarunnu.
splies veriyantukalum lokkeshanukalum.
yubi 3 eiii-aatts" traanskript ulppede muzhuvan "elenkaattu" traanscriptum traanskript cheyyaamenkilum, vividha exonukal ulppeduthunnathinum ozhivaakkunnathinum ithu palappozhum splies cheyyappedunnu. vyathyastha tissue tharangalilum saahacharyangalilum vyathyastha splies vakabhedangal prakadippikkunnu. mikkappozhum, purkinje koshangal, hippocampal neuronukal thudangiya mudranam cheytha cns koshangalil eathenkilum tharatthilulla neuronukalilo" vyakthamaanennu karuthappedunnu. ennirunnaalum, eee traanscriptinte thaazhekkum mukalilekkum ulla bhaagangalkk speshiyodemboral niyanthranamund. koodaathe "jenal oof neuro sayans".
mouse bhroonangalil, koyittaminu sesham ekadesham 7 divasam kazhinju blaastosistukalil "snoorf/snrpn" exonukal kandethukayum vikasanathiludaneelam prakadippikkunnathu thudarukayum cheythu. snoorf/ezz. enn. aarr. pii. enn" exonukal vikasana samayat sii. enn. ezz tissuevil parimithappedutthiyirikku, pinneedu praayapoorthiyaakumbol maathrame mattu tissue prakadippikkukayulloo. sesham exonukal 10 divasam poost koyittem vare kandethiyitla, avayude aavishkaaravum vikasana samayat cnsil parimithappedutthiyirunnu. pothuve, neurogenesisinte prarambha ghattangalil ghattangalil kandethumbol "snoorf/snrpn" vyathyasthamallatha mungamikalaaya koshangalilum vyathyaasathinte kaalathudaneelavum prakadippikkunnu. yuu. sii. ezz. sii. genome brouser anusarichu kuranjathu 10 vyathyastha splies isophomukalenkilum undu.
oru patanam anusarichu, "yubi 3 eiii" yeei nerittu ovarlaappu cheiyunna splies vakabhedam cytoplaasathil kaanapedunnu.
rund alleelukalilum aavishkaaram thadayunnu.
maathru, pithru alleelukalil neuronukalilo" enna deferential expression niyantrikkaan oru prathyeka impinting sentar klasttar sahaayikkumenn karuthappettirunnu. mudranam cheiyunna kendrangalil (aii. sii. ezz) rund mekhalakalundu, avaa eiii. ezz., pii. dablyu. esumaayi bandhappettirikkunnu-eiii. ezz. aii. sii, pii. dablyu. ezz. aii. sii. chuttumulla jeenukalum pradeshangalum prakadippikkaan kazhiyumo ennu nirnnayikkunna niyanthrana pradesangalaanu eee mudranam kendrangal, avaa maathru, pithru alleelukalil kaanapedunnu. maathru, pithru jeenukalile deferential methylation paattenukal palappozhum mudranayumaayi bandhappettirikkumbol, rund alleelukalilum aas-aisi methylated aayi thudarunnu. ennirunnaalum, ayalrajyamaaya pii. dablyu. ezz-aii. sii maathru alleelil methylate cheythirikkunnuvenkil pithru alleelil methylate cheyyaathe thudarunnu.
lncat", "ube3a-ats" ennivayude padaprayogam niyanthrikkunnath pws-ic aanennu samshayikkunnu. pdablues-aisi illaathaakkiya elikalil, elikalil enna padaprayogam kurayunnu. kendra neural sisttathil, pii. dablyu. ezz-aii. sii. methylated allatha pithrusasyangalil ninnaan neuronukalilo" mungananayode prakadippikkunnathu. maruvashathu, pdablues-aisi methylated aayirikkunna maathru alleelil, sesham prakadippikkunnilla, ithu pdablues-aisinte methylation enganeyengilum sesham expressione thadayunnuvennu soochippikkunnu. bhroona stem cellukalile methyl traansfaresukal thakarth pdablues-aisinte methylation thadayunnathu "uba "yubi enna bialelic expression maathru alleelile "uba 3eiii" nishabdamaakkunnathinum kaaranamakunna niravadhi padanangal ithine pinthunaykkunnu.
ennirunnaalum, maathru "yubi 3 eiii-aatts"-nte aavishkaaram thadayunnathil ulppedunna eaka prakriya methylation allah. maathru alleelile "elenkaattu", "yubi "yubi enniva nishabdamaakkaan sahayikkunna mattu proteinukalumaayi mudranam cheiyunna domainukal edapedumennu prathekshikkunnu. udaaharanathinu, rettu syndrome rogikalil rogikalil puratthaakumbol, puratthaakumbol ennathu bialelic aayi prakadippikkappedunnu, ithu maathru alleelil ninnulla pithaavinte yude aavishkaaram kuraykkunnu.
koottiyidi model.
elenkaattu"-nte sesham pithaavinte pithaavinte-yeei engane nishabdamaakkunnuvennu vishadeekarikkunna moonnu modalukal nilavil undu-koottiyidi model, rna-dna interaakshan model, eratta strended rna interference model. eee modalukal modalukal ennathinu nerittu pradarshippichittillengil, eee reethikal vazhi mattu prakrithidatha antisense traanscriptukal nishabdamaakkunnathinulla thelivukalude adisthaanathil avaa vishwasaneeyamaayi kanakkaakkappedunnu. ennirunnaalum, ettavum puthiya pinthunaa padanangal kaaranam koottiyidi model mikkavarum drishyamaakunnu.
koottiyidi model oru kaarinu maathram mathiyaya veethiyulla rodaayi kanakkakkaam. oru smart kaar oru dishayil ninnu sanjarikkukayum maruvashathu ninnu oru kalappa oduvil koottiyidikkukayum cheiyunnu. koottiyidichathinushesham, smart kaar munnott neengumbol kalappa pinnilekku thallunnu. kaanikkunnu enna koottiyidi maathrkayil, rna polymeraseukal (arnaps) transcription samayat sensilum antisans templettukalilum parasparam sanjarikkunnu. sense antisense templettukalum pithaavinte, sesham ennivaykku ovarlaappu cheiyunnu. rund transcription kumilakal koottiyidikkukayum "yubi 3 eiii-aatts" ennu traanskript cheiyunna rnap, kalappayayathinaal, "yubi 3 eiii" (smart kaar) traanskript cheiyunna rnap templettil ninnu pinnilekkum oduvil oof cheyyaanum idayaakkukayum cheyyum. ithu ithu poornna transcription thadayunnu.
sameepakaalathe rund padanangalil ninnaan eee modalinu pinthuna labhikkunnath. antisense strandle prakadippikkunna jeenukalaal ovarlaappu cheyyappetta sense straandukalile jeenukalude transcription aadya patanam parishodhichu. ovarlaappu cheiyunna pradesham ethratholam dairkhyamulluvo, sense straandinte transcription athratholam kaaryakshamamalla, ithu oru strandile transcription matte strandile transcriptione thadassappeduthunnuvenna soochippikkunnu. mattoru patanam aattomik fozhsu microscopy upayogichu oru template transcribucheyyunna aarr. enn. eiii. pii. kall thammilulla koottiyidi nerittu nireekshichu. dna shakalangalil aarnaappukal nirthukayum mattu neelamulla aarnaappukalumaayi koottiyidikkukayum cheythu. koottiyidichu udan thanne rund aarr. enn. eiii. pii. kall nirthalaakkunnathum oru aarr. enn. eiii. pii. pinnott pookunnathum chithrangalil kaanikkunnu.
kaanikkunnu ennathinu vendi eee padanangal nadathiyittillengilum, eee lokkasil transcription nireekshikkaan aattomik fozhsu microscopy upayogikkunnathu sesham vazhi pithaavinte yadhaarthathil engane nishabdamaakkappedunnu ennathinekkurichulla ulkkaazhcha nalkum. nalkum ykkayi eee modalukal sthireekarikkunnathinu kooduthal padanangal ippozhum aavasyamaanu.
parasparavirudhamaaya padanangal.
pithaavinte "yubi 3 eiii" nishabdathayil "yubi 3 eiii-aatts" ulppettirikkaamenna ashayathe niravadhi padanangal pinthunaykkumbol, mattu padanangal ithinu virudhamaanu. oru patanam prathyekichum "yubi 3 eiii-aatts" enna "yubi 3 eiii" yude inn sis nishabdathaykkethire vaadikkunnu. eee padanatthil, maathru "yubi 3 eiii" alleel illaathaakkiyappol, pithru "yubi 3 eiii-aatts" padaprayogatthil vardhanavu kandu. ithu soochippikkunnathu, pithaavinte pithaavinte pithaavinte maathaavinte niyanthrikkunnathinupar, maathaavinte maathaavinte enganeyengilum pithaavinte pithaavinte enna padaprayogatthe adichamarthunnu, orupakshe "sisil" ennathinekkaal "transil". eee jeenukalude maathru, pithru samaroopa pradeshangal thammilulla edapedal interface samayat manushyarilum elikaludeyum koshangalil nireekshikkappettu.
inn trans" nishabdatha vishadeekarikkunnathinula oru samvidaanathil pithru "yubi 3 eiii-aatts" rna maathru "yubi 3 eiii" marna thammilulla edapedal ulppedunnu. maathru pithaavinte marnah pithaavinte sesham rnaumaayi samvadikkukayum eee rund traanscriptukaludeyum sthiratha kuraykkukayum cheyyaan saadhyathayund. saadhyathayund illaathe sesham maathram nirmmikkumbol, sesham kooduthal sthirathayullathaayi maarunnu.
maarunnu enna padaprayogam achadicha pradeshangalil sambhavikkunnillenn mattoru patanam soochippikkunnu. "inn sittuvil" "sankaravalkkaranangal purkinje koshangalilo hippocampal neuronukalilo" neuronukalilo" "velippeduthiyittilla". ennirunnaalum, "snoorf/snrpn" maayi poruthappedunna mattu upstream exonukal prakadippikkappettu, ithu koottiyidi model ippozhum sambhavikkaamenn soochippikkunnu. athinaal kooduthal gaveshanam aavasyamaanu.
bhaviye.
bhaviye vazhi pithaavinte padaprayogam niyantrikkaanulla saadhyatha upayogikkaan niravadhi padanangal sramichittundu. kaaranam, pithaavinte pdablues-aisi methylated allah, ithu "yubi 3 eiii-aatts" expression anuvadikkunnuvennu karuthappedunnu. athinaal, pdablues-aisiyude methylation saadhyamaanengil, "yubi 3 eiii-aats" transcription nirodhikkaamaayirunnu, ithu maathru alleelil ninnulla aavishkaarathinte abhavam nikathaan pithru alleelil ninnulla "yubi 3 eiii" expression anuvadikkunnu. niravadhi rogikalumaayi oru varshathe patanam nadatthi. eee rogikale beettain, metapholin, kriyetteen, vitaamin bii 12 supplementukal enniva ulppedunna bhakshanakramathe prothsaahippikkunna methylation nalki. ennirunnaalum, oru varshathinusesham, eee rogikalil methylation reethikal mariyittilla.
mattoru patanam vividha marunnukalude oru valia library pareekshikkukayum mouse neuronukalilum elikalilum pithruthulyamaaya "yubi 3 eiii" yude aavishkaaram vardhippikkunna niravadhi topoisomerase I, II inhibittarukal thirichariyukayum cheythu. topoisomerase inhibittarukal chemotherapic aayi vyaapakamaayi upayogikkunnu, koodaathe replication forkine thadassappeduthunna eratta strand breakkukal prerippikkunnathiloode replicating cellukal apoptosisinu vidheyamaakkunnu. ennirunnaalum, pithaavinte pithaavinte sajeevamakkunnathinulla avarude pravartthana samvidaanam ithuvare arivayittilla, pakshe mayakkumarunnu chikilsaykku sesham sesham traanscriptukal kuranjathinaal kuranjathinaal transcription edapedal ulppettekkaam. kuranja nanomolar shreniyil ettavum phalapradamaaya toppotekkanekkurich padikkaan samgham prathyekamaayi thiranjedutthu, koodaathe niravadhi tharam arbudangal chikilsikkunnathinu ithinakam thanne bhakshya, marunnu administration amgeekarichittundu.

