Methylation ea DNA ho Tlhaloso ea Gene
Methylation ea DNA ke e 'ngoe ea mekhoa ea bohlokoa ka ho fetisisa ea epigenetic, e laolang hore na liphatsa tsa lefutso li hlahisoa neng le ka matla hakae ntle le ho fetola tatellano ea motheo oa DNA ka boeona. Ka mantsoe a mang, tlhahisoleseling ea liphatsa tsa lefutso e lula e tšoana, empa "ho bala" ha eona ho ka fetoha. Ts'ebetso ena e bapala karolo e kholo nts'etsopele ea lesea le sa tsoa emoloa, phapang ea lisele, tlhokomelo ea boitsebiso ba lisele, esita le ho kenella ha eona mafung a fapaneng a kang mofetše. Ho utloisisa methylation ea DNA ho re thusa ho bona hore taolo ea liphatsa tsa lefutso ha se feela taba ea hore na re na le liphatsa tsa lefutso life, empa hape le hore na liphatsa tseo tsa lefutso li "kenngoa tšebetsong" kapa "khutsisoa" joang maemong a itseng a baeloji.
Methylation ea DNA ke eng?
Methylation ea DNA ke ho eketsoa ha sehlopha sa methyl (–CH₃) ho molek'hule ea DNA. Liphoofolong tse nang le lesapo la mokokotlo, phetoho ena hangata e etsahala metheong ea cytosine e lateloa ke guanine (e bitsoang libaka tsa CpG, ho tsoa ho "C-phosphate-G"). Cytosine libakeng tsa CpG e ka fetoloa methylation ho ba 5-methylcytosine (5mC). Le hoja ho bonahala ho le bonolo, ho eketsoa ha sehlopha sena se senyenyane ho ka fetola tšebelisano ea DNA le liprotheine tse laolang phetolelo, ka hona ho fetola maemo a tlhahiso ea liphatsa tsa lefutso.
Methylation ea DNA e oela tlas'a epigenetics hobane e futsitsoe nakong ea karohano ea sele (mitosis) empa e ka fetoloa 'me ha e fetole tatellano ea nucleotide. Sena se bolela hore lisele tse peli tse nang le DNA e tšoanang - mohlala, sele ea sebete le sele ea methapo - li ka ba le mekhoa e fapaneng ea methylation e etsang hore li hlahise lihlopha tse fapaneng tsa liphatsa tsa lefutso.
Li-enzyme tse laolang methylation: DNMT
Mokhoa oa methylation ha o etsahale ka boithatelo, empa ho e-na le hoo o tataisoa ke li-enzyme tsa DNA methyltransferase (DNMT). Ka kakaretso, ho na le li-DNMT tse 'maloa tsa bohlokoa:
1. DNMT3A le DNMT3B: di ikarabella bakeng sa methylation e ntjha, e leng ho thehwa ha dipaterone tse ntjha tsa methylation nakong ya ntshetsopele ya pele ya disele le phapang.
2. DNMT1: e bapala karolo ho methylation ea tlhokomelo, e leng ho boloka mekhoa ea methylation kamora ho ikatisa ha DNA e le hore lisele tsa morali li rue "memori" ea epigenetic ea sele ea motsoali.
Ha DNA e ikatisa, methylation e itseng e ka "lahleha" hobane khoele e ncha ha e na methylation. DNMT1 e lemoha DNA e nang le hemimethylated (khoele ea khale e na le methylation, khoele e ncha ha e na eona) 'me e eketsa methyl ho khoele e ncha e le hore mokhoa oa methylation o lule o le teng.
Ka lehlakoreng le leng, ho tlosoa ha methyl ho ka etsahala ka ditsamaiso tse sa sebetseng (mohlala, ho hloleha ha tlhokomelo nakong ya karohano ya sele) kapa ka mafolofolo ka dienzyme tse kang lelapa la TET (Ten-Eleven Translocation) tse kopanyang 5mC mme di baka phallo ya tokiso ya DNA ho tsosolosa di-cytosine tse sa nang le methyl.
Kamano pakeng tsa methylation ea DNA le polelo ea liphatsa tsa lefutso
Tšusumetso ea methylation ho tlhahiso ea liphatsa tsa lefutso e itšetlehile haholo ka sebaka sa methylation ho genome.
1. Methylation ho promoter: e atisa ho khutsisa liphatsa tsa lefutso
Mohlohlelletsi ke sebaka sa DNA haufi le qalo ea jini e sebetsang e le "ntlha ea qalo" bakeng sa ho ngoloa ha mongolo. Bahlohlelletsi ba bangata ba jini ba na le bongata bo phahameng ba CpGs, tse bitsoang lihlekehleke tsa CpG. Haeba sehlekehleke sa CpG ho mohlohlelletsi se na le methylated, ho ngoloa ha jini hangata hoa fokotseha kapa ho emisa. Sena se etsahala ka mekhoa e 'meli e meholo:
– Ho thibela mabaka a ho ngolwa ha mongolo: mabaka a mang a ho ngolwa ha mongolo a ke ke a kgomarela DNA haeba libaka tsa ona tsa ho lemoha di na le methylated.
– Ho bokella liprotheine tse tlamang methyl: Liprotheine tse kang MeCP2 li ka lemoha DNA e nang le methyl ebe li bokella li-complex tsa repressor (mohlala, histone deacetylase/HDAC). Ka lebaka leo, chromatin e ba nyane haholo (heterochromatin), 'me mochini oa transcription o thatafalloa ho fihlella liphatsa tsa lefutso.
2. Methylation 'meleng oa liphatsa tsa lefutso: e ka amahanngoa le liphatsa tsa lefutso tse sebetsang
Hoa thahasellisa hore methylation ea 'mele oa liphatsa tsa lefutso hangata e fumanoa liphatseng tsa lefutso tse hlahisoang ka mafolofolo. Khopolo-taba e 'ngoe ke hore methylation ea 'mele oa liphatsa tsa lefutso e thusa ho thibela ho qalisoa ha phetolelo "e sa lokelang" 'me e ntlafatsa botšepehi ba phetolelo. Kahoo, methylation ha se kamehla e amanang le ho khutsisa; moelelo oa liphatsa tsa lefutso o bohlokoa.
3. Methylation ea li-enhancer le likarolo tse ling tsa taolo
Li-enhancer ke likarolo tsa DNA tse ka eketsang tlhahiso ea liphatsa tsa lefutso hole. Methylation ea li-enhancer hangata e fokotsa ts'ebetso ea enhancer, ka hona e fokotsa tlhahiso ea liphatsa tsa lefutso tse reretsoeng. Liphetoho ho methylation ea enhancer li ka fana ka mokhoa o potlakileng oa hore lisele li fetole mananeo a tsona a liphatsa tsa lefutso ho latela matšoao a nts'etsopele kapa a tikoloho.
Methylation ea DNA nts'etsopele le phapang
Nakong ea kholo ea lesea le sa tsoa emoloa, ho etsahala "phetoho e kholo" ea mekhoa ea methylation. Mothating o itseng, methylation ea genomic e fokotseha lefatšeng ka bophara, ebe e itsosa hape ka phapang. Ts'ebetso ena e lumella lisele tsa motheo tsa lesea le sa tsoa emoloa ho boloka ho tenyetseha, ebe butle-butle li notlela boitsebiso ba tsona ba sele—mohlala, lisele tsa mesifa, lisele tsa epithelial, kapa li-neuron—ka ho khutsisa liphatsa tsa lefutso tse sa amaneng le mosebetsi oa tsona.
Mohlala o bonolo: liphatsa tsa lefutso tse hlokahalang liseleng tsa methapo li ka sebetsa hobane li-promoter tsa tsona ha li na methyl e ngata li-neuron, empa liphatsa tsa lefutso tse tšoanang li ka khutsisoa liseleng tsa sebete ka methylation ea promoter. Kahoo, methylation e thusa ho boloka botsitso ba nako e telele ba boitsebahatso ba sele.
Ho hatisoa ha genomic le ho se sebetse ha chromosome ea X
Methylation ea DNA le eona e bohlokoa liketsahalong tse itseng tsa epigenetic:
– Ho hatisoa ha liphatsa tsa lefutso ke tlhahiso ea liphatsa tsa lefutso tse itšetlehileng ka batsoali ba tsona (ba 'm'ae kapa ba ntate). Liphatseng tse itseng tsa lefutso, allele e le 'ngoe e khutsisoa ka methylation, e le hore ho hlahe allele ea ntate kapa ea 'm'ae feela.
– Ho se sebetse ha chromosome ea X ho liphoofolo tse anyesang tse tšehali ke mokhoa oa ho tima e 'ngoe ea li-chromosome tsa X ho leka-lekanya kabo ea liphatsa tsa lefutso le ea tse tona. Methylation e bapala karolo ea ho boloka boemo bona bo sa sebetseng, hammoho le liphetoho tsa histone le RNA e sa ngoleng khoutu.
Mekhoa ena e 'meli e bontša hore methylation ha se feela taolo ea ho lokisa lintho hantle, empa ke mokhoa oa "switch" o ka thehang mekhoa e tsitsitseng ea tlhahiso ea liphatsa tsa lefutso.
Methylation ea DNA le lefu
Liphetoho mekhoeng ea methylation li ka sitisa taolo ea liphatsa tsa lefutso 'me tsa kenya letsoho mafung.
1. Kankere
Kankere, mekhoa e 'meli e bonahalang e hanyetsana hangata e hlaha hammoho:
– Global hypomethylation: ho fokotseha ha methylation libakeng tse ngata tsa genome ho ka lebisa ho se tsitse ha genome, ho kenngwa tshebetsong ha dikarolo tse ka fetolwang, le keketseho ya diphetoho.
– Hypermethylation ea li-promoter tsa liphatsa tsa lefutso tse hatellang hlahala: Li-promoter tsa liphatsa tsa lefutso tse lokelang ho thibela kholo ea lisele li ka ba le methylation e feteletseng, e leng se khutsisang liphatsa tsa lefutso. Ka lebaka leo, lisele li ka ata habonolo ka mokhoa o sa laoleheng.
Kaha methylation e ka fetoloa, mekhoa ea phekolo ea epigenetic e kang li-inhibitor tsa DNMT e 'nile ea sebelisoa mefuteng e itseng ea mofetše ho leka ho "thibela" liphatsa tsa lefutso tse khutsitseng.
2. Mathata a methapo le a ntshetsopele
Liprotheine tse tlamang DNA tse nang le methylated tse kang MeCP2 li hokahantsoe le ts'ebetso ea methapo ea kutlo; liphetoho tse bang teng ho MECP2 li ka baka Rett syndrome. Sena se fana ka maikutlo a hore tlhaloso ea methylation e bohlokoa joalo ka methylation ka boeona.
3. Litšusumetso tsa tikoloho le mokhoa oa bophelo
Phepo e nepahetseng (mohlala, folate e le mofani oa methyl), ho pepesehela litšila, khatello ea maikutlo le lintlha tse ling tsa mokhoa oa bophelo ho ka susumetsa mekhoa ea methylation. Le hoja likamano tsa sesosa le phello ho batho hangata li rarahane, lithuto tse ngata li bontša hore tikoloho e ka siea "letšoao la epigenetic" le ka 'nang la ama kotsi ea mafu.
Methylation ea DNA e ithutoa joang?
Patlisiso ea methylation ea DNA e ntse e hatela pele ka potlako ka lebaka la theknoloji ea tatellano. Mekhoa e tsebahalang e kenyelletsa:
– Ho latellana ha Bisulfite: Kalafo ea Bisulfite e fetola cytosine e sa methylated ho ba uracil, ha 5mC e ntse e le cytosine. Ka ho bapisa liphetho tsa tatellano, bafuputsi ba ka 'mapa oa libaka tsa methylation ka qeto e phahameng.
– Methylation array: e lekanya methylation libakeng tse makholo a likete tsa CpG ka potlako le ka mokhoa o itekanetseng.
– Liteko tse thehiloeng ho PCR tse ikhethileng ka methylation: li thusa ho leka boemo ba methylation ea liphatsa tsa lefutso tse itseng, mohlala lithutong tsa biomarker tsa mofetše.
Liphetho tsa tekanyo ea methylation li hokahanngoa le data ea tlhahiso ea liphatsa tsa lefutso (transcriptome) ho utloisisa tšusumetso ea tsona ea ts'ebetso.
Qetello
Methylation ea DNA ke karolo ea bohlokoa ea taolo ea epigenetic e susumetsang tlhahiso ea liphatsa tsa lefutso ka maemo: hangata e hatella liphatsa tsa lefutso ha li etsahala ho li-promoter, empa e ka ba le mesebetsi e meng ha e etsahala 'meleng oa liphatsa tsa lefutso kapa libakeng tse ntlafatsang. Ka ts'ebetso ea li-enzyme tsa DNMT le litsamaiso tsa demethylation, lisele li ka theha, tsa boloka, le ho fetola mekhoa ea tlhahiso ea liphatsa tsa lefutso ho latela litlhoko tsa nts'etsopele le likarabelo tsa tikoloho. Ha tsamaiso ena e sitisoa, kotsi ea lefu—haholo-holo kankere le mathata a nts'etsopele—e ka eketseha. Ka lebaka la tlhaho ea eona e matla le e ka fetoloang, methylation ea DNA ha se taba ea motheo feela baelojing ea limolek'hule empa hape ke tšimo e tšepisang bakeng sa tlhahlobo le mekhoa ea phekolo e thehiloeng ho epigenetic.
Haeba o lakatsa, nka fetola sengoloa sena hore e be mofuta o batlang o le wa thuto e eketsehileng (o nang le diqotso le mantswe a botekgeniki a mangata) kapa mofuta o tsebahalang bakeng sa babadi ba kakaretso.
