DNA Methylation muGene Expression
DNA methylation ndeimwe yenzira dzinonyanya kukosha dze epigenetic, inodzora kuti gene rinobudiswa riini uye sei pasina kuchinja DNA base sequence pachayo. Nemamwe mashoko, ruzivo rwemajini runoramba rwakafanana, asi "kuverenga" kwaro kunogona kuchinja. Maitiro aya anoita basa guru mukukura kwemwana ari mudumbu, kusiyana kwemasero, kuchengetedza hunhu hwenyama, uye kunyange kubatanidzwa kwayo muzvirwere zvakasiyana-siyana zvakaita sekenza. Kunzwisisa DNA methylation kunotibatsira kuona kuti kudzorwa kwemajini hakusi kungotaura nezvemajini atinawo chete, asiwo kuti majini iwayo "anovhurwa" sei kana "kunyaradzwa" mumamiriro ezvinhu chaiwo ehupenyu.
Chii chinonzi DNA methylation?
DNA methylation kuwedzerwa kweboka remethyl (–CH₃) kune molekyuru yeDNA. Muzvisikwa zvine mapfupa emusana, shanduko iyi inowanzoitika pa cytosine bases ichiteverwa ne guanine (inonzi CpG sites, kubva ku "C-phosphate-G"). Cytosine panzvimbo dzeCpG inogona kusanganiswa kuita methylated kuita 5-methylcytosine (5mC). Kunyangwe zvichiita sezviri nyore, kuwedzerwa kweboka diki iri kunogona kuchinja kudyidzana kweDNA nemapuroteni anotonga transcription, nokudaro kuchichinja mazinga ekutaura kwemajini.
DNA methylation inowira pasi pe epigenetics nekuti inogara nhaka panguva yekupatsanurwa kwemasero (mitosis) asi inodzoreka uye haichinji kurongeka kwe nucleotide. Izvi zvinoreva kuti masero maviri ane DNA imwechete - semuenzaniso, chiropa nesero retsinga - anogona kuva nemapatani akasiyana emethylation anoita kuti aratidze majini akasiyana.
Ma enzyme anodzora methylation: DNMT
Maitiro e methylation haaitiki ega, asi anotungamirwa nema enzymes eDNA methyltransferase (DNMT). Kazhinji, kune akawanda maDNMT akakosha:
1. DNMT3A neDNMT3B: zvinopa basa rekuita kuti methylation iite itsva, kureva kuumbwa kwemapatani matsva emethylation panguva yekukura nekusiyana kwemasero.
2. DNMT1: inoita basa rekuchengetedza methylation, kureva kuchengetedza maitiro emethylation mushure mekudzokororwa kweDNA kuitira kuti masero emwanasikana agare nhaka "ndangariro" ye epigenetic yesero remubereki.
Kana DNA ikadzokorora, imwe methylation inogona "kurasika" nekuti tambo itsva haina methylated. DNMT1 inoziva hemimethylated DNA (tambo yekare ine methylated, tambo itsva haina) uye inowedzera methyl kune tambo itsva kuitira kuti patani yemethylation irambe iripo.
Kusiyana neizvi, kubviswa kwemethyl kunogona kuitika kuburikidza nemaitiro asina kugadzikana (semuenzaniso, kutadza kugadzirisa panguva yekupatsanurwa kwemasero) kana kuburikidza nema enzymes akadai semhuri yeTET (Ten-Eleven Translocation) iyo inooxidize 5mC uye inokonzeresa DNA repair cascade kuti idzorere unmethylated cytosines.
Hukama huripo pakati peDNA methylation uye kugadzirwa kwemajini
Mhedzisiro yemethylation pakuonekwa kwemajini inoenderana zvikuru nenzvimbo yemethylation mugenome.
1. Methylation pa promoter: inowanzo nyaradza majini
Chinosimudzira gene inzvimbo yeDNA iri pedyo nekutanga kwegene inoshanda se "nzvimbo yekutanga" yekunyora. Mazhinji evanokurudzira majini ane huwandu hwakawanda hweCpGs, hunonzi zvitsuwa zveCpG. Kana chitsuwa cheCpG chiri muchikamu chinosimudzira methylated, kunyorwa kwemajini kunowanzo derera kana kutomira. Izvi zvinoitika kuburikidza nenzira mbiri huru:
– Zvinodzivisa zvinhu zvinonyora zvinyorwa: zvimwe zvinhu zvinonyora zvinyorwa hazvigoni kubatana neDNA kana nzvimbo dzazvo dzekuzivikanwa dzakasanganiswa nemethyl.
– Kuunganidza mapuroteni anosunga methyl: Mapuroteni akadai seMeCP2 anogona kuziva DNA ine methylation uye obva aunganidza ma repressor complexes (semuenzaniso, histone deacetylase/HDAC). Nekuda kweizvozvo, chromatin inova diki (heterochromatin), uye michina yekunyora inonetseka kuwana majini.
2. Methylation mumuviri wemajini: inogona kuenderana nemajini anoshanda
Zvinofadza kuti, methylation yemuviri wemajini inowanzo kuwanikwa mumajini anoratidzwa nemajini. Imwe fungidziro ndeyekuti methylation yemuviri wemajini inobatsira kudzivirira kutanga kwekunyora "kusina nzvimbo" uye inovandudza kutendeseka kwekunyora. Saka, methylation haisi nguva dzose inofanana nekunyarara; mamiriro ejini akakosha.
3. Kusanganiswa kwezvinosimudzira uye zvimwe zvinhu zvinodzora methylation
Zvinosimudzira muviri zvinhu zveDNA zvinogona kuwedzera kugadzirwa kwemajini zviri kure. Kuwedzerwa kwemethylation yezvinowedzera muviri kunowanzo deredza mashandiro ekuwedzera muviri, nokudaro zvichideredza kugadzirwa kwemajini akakosha. Kuchinja kwemethylation inosimudzira muviri kunogona kupa nzira yekukurumidza yekuti masero agadzirise zvirongwa zvavo zvemajini kuti zvienderane nezviratidzo zvekukura kana zvakatipoteredza.
DNA methylation mukukura nekusiyanisa
Munguva yekukura kwemwana ari mudumbu, "kugadziriswazve" kukuru kwemaitiro emethylation kunoitika. Pane imwe nhanho, genomic methylation inoderera pasi rose, yozozvigadzirisa pachayo nekusiyana. Maitiro aya anobvumira masero ekutanga emwana ari mudumbu kuchengetedza kuchinjika, ozovhara zvishoma nezvishoma kuzivikanwa kwemasero avo—semuenzaniso, masero emhasuru, masero eepithelial, kana ma neuron—nekunyaradza majini asina basa nemashandiro awo.
Muenzaniso wakapfava: majini anodiwa mumasero etsinga anogona kushanda nekuti mapromoter awo haana methyl yakakwana mumasero etsinga, asi majini akafanana anogona kunyaradzwa mumasero echiropa kuburikidza nepromoter methylation. Saka, methylation inobatsira kuchengetedza kugadzikana kwenguva refu kwekuzivikanwa kwemasero.
Kuisa genomic uye kusashanda kweX chromosome
DNA methylation inokoshawo mune zvimwe zviitiko zve epigenetic:
– Kuiswa kwemajini mumasero ndiko kuratidzwa kwemajini kunoenderana nevabereki vavo (vaamai kana baba). Mune mamwe majini, allele imwe chete inodzimwa kuburikidza nemethylation, zvekuti allele yebaba kana yaamai chete ndiyo inoburitswa.
– Kusashanda kwechromosome yeX mumhuka dzinoyamwisa dzechikadzi inzira yekudzima imwe yemachromosome eX kuti ienzanise kugoverwa kwemajini nekwevanhurume. Methylation inoita basa rekuchengetedza mamiriro aya asina simba, pamwe chete nekuchinja kwehistone uye RNA isina coding.
Maitiro maviri aya anoratidza kuti methylation haisi kungogadzirisa zvinhu chete, asi inzira ye "switch" inogona kugadzira maitiro akagadzikana ekutaura kwemajini.
DNA methylation uye chirwere
Kuchinja kwemagadzirirwo emethylation kunogona kukanganisa kurongeka kwemajini uye kukonzera zvirwere.
1. Gomarara
Mugomarara, maitiro maviri anoita seanopikisana anowanzo itika pamwe chete:
– Global hypomethylation: kudzikira kwemethylation munzvimbo dzakasiyana dzegenome kunogona kukonzera kusagadzikana kwemajini, kushanda kwezvinhu zvinoshanduka, uye kuwedzera kwekuchinja kwezvinhu.
– Hypermethylation yezvinosimudzira majini zvinodzvinyirira bundu: Zvinosimudzira majini zvinofanira kudzivirira kukura kwemasero zvinogona kunyanyisa methylation, zvichinyaradza jini. Nekuda kweizvozvo, masero anogona kuwedzera zviri nyore zvisingadzoreki.
Nekuti methylation inogona kugadziriswa, mishonga ye epigenetic yakadai seDNMT inhibitors yakashandiswa mune mamwe marudzi ekenza kuyedza "kuvhura" majini akavharirwa.
2. Matambudziko etsinga nekukura
Mapuroteni anosunga DNA ane methylated akadai seMeCP2 anobatanidzwa nekushanda kwetsinga dzeropa; shanduko muMECP2 dzinogona kukonzera Rett syndrome. Izvi zvinoratidza kuti kududzirwa kwemethylation kwakakosha semethylation pachayo.
3. Zvinopesvedzera zvakatipoteredza uye mararamiro
Kudya kunovaka muviri (semuenzaniso, folate semupi wemethyl), kusangana nezvinhu zvinosvibisa, kushushikana, nezvimwe zvinhu zvinoita kuti munhu ararame zvinogona kukanganisa maitiro emethylation. Kunyange hazvo hukama hwevanhu huchiwanzova hwakaoma, zvidzidzo zvakawanda zvinoratidza kuti zvakatipoteredza zvinogona kusiya "chiratidzo che epigenetic" chinogona kukanganisa njodzi yezvirwere.
DNA methylation inodzidzwa sei?
Tsvagiridzo yeDNA methylation iri kufambira mberi nekukurumidza nekuda kwetekinoroji yekutevera. Nzira dzakakurumbira dzinosanganisira:
– Kutevedzana kweBisulfite: Kurapa kweBisulfite kunoshandura cytosine isina methylated kuita uracil, nepo 5mC ichiramba iri cytosine. Nekuenzanisa mhedzisiro yekutevedzana, vaongorori vanogona kuyera nzvimbo dzemethylation ne resolution yepamusoro.
– Methylation array: inoyera methylation pamazana ezviuru zveCpG nzvimbo nekukurumidza uye nemutengo wakaderera.
– Kuyedza kwePCR kwakavakirwa paMethylation-specific PCR: kunobatsira pakuedza mamiriro emethylation emajini chaiwo, semuenzaniso muzvidzidzo zve biomarker yekenza.
Mhedzisiro yekuyerwa kwemethylation inobva yabatanidzwa nedata remagene expression (transcriptome) kuti inzwisise mashandiro adzo.
Mhedziso
DNA methylation chinhu chakakosha mukutonga kwe epigenetic chinopesvedzera kutaurwa kwemajini zvichienderana nemamiriro ezvinhu: inowanzo dzora majini painoitika kuma promoters, asi inogona kuita mamwe mabasa painoitika mumuviri wemajini kana munzvimbo dzinosimudzira. Kuburikidza nekushanda kwema enzymes eDNMT uye masisitimu e demethylation, masero anogona kugadzira, kuchengetedza, uye kugadzirisa maitiro ekutaura kwemajini zvichienderana nezvinodiwa pakukura uye mhinduro dzenharaunda. Kana sisitimu iyi ikakanganiswa, njodzi yezvirwere - kunyanya kenza uye matambudziko ekukura - inogona kuwedzera. Nekuda kwehunhu hwayo hwekuchinja uye hunogona kudzoreredzwa, DNA methylation haisi nyaya huru mu molecular biology chete asiwo inzvimbo inovimbisa yekuongorora nekurapa kwakavakirwa pa epigenetic.
Kana muchida, ndinogona kugadzirisa chinyorwa ichi kuita shanduro yedzidzo yepamusoro (ine zvirevo uye mazwi ehunyanzvi) kana shanduro inozivikanwa nevaverengi vazhinji.
