JP2008521389A - メチル化dnaを検出する手段、及び方法 - Google Patents
メチル化dnaを検出する手段、及び方法 Download PDFInfo
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- JP2008521389A JP2008521389A JP2007541869A JP2007541869A JP2008521389A JP 2008521389 A JP2008521389 A JP 2008521389A JP 2007541869 A JP2007541869 A JP 2007541869A JP 2007541869 A JP2007541869 A JP 2007541869A JP 2008521389 A JP2008521389 A JP 2008521389A
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Abstract
Description
私たちのゲノムを「つづる」4つの塩基−アデニン、グアニン、シトシン、及びチミンは別として、複製後のDNAの一時的変異により産生される5番目の塩基もある。DNAメチルトランスフェラーゼ(DNMT)は、メチル供与体S−アデノシルメチオニンからシトシン環へのメチル基の移転を触媒し得る、そしてその結果、5−メチルシトシン塩基を形成する。特定のシトシン残基が哺乳類において修飾され、それは、DNA配列のグアノシン残基の前にある(CpGジヌクレオチド)(Singal,Blood93(1999),4059-4070);Robertson,Nat.Rev.Genet.1(2000),11−19;Ng,Curr.Opin.Genet.Dev.(2000),158−163;Razin,EMBO J.17(1998),4905−4908)。当該CpGジヌクレオチドのメチル化は、一般的に、安定した転写抑制と関連し、おそらく、非コードゲノムの大部分、及びトランスポゾン、繰り返し体、ウイルス性挿入部分の如き潜在的に有害な配列は転写されないといった事実を導く。CpGジヌクレオチドが、ゲノム中において、非常に遍在していることは興味深い(Singal(1999),loc.cit,Robertson(2000),loc.cit.,Ng(2000),loc.cit.,Razin(1998),loc.cit.)。
DNAメチル化パターンが胚形成の過程中でどのように確立されるのか、及びCpGメチル化がどのようにゲノム中に維持され、調節されるのかは、一部しかわかっていない(Singal(1999),loc.cit,Ng(2000),loc.cit.,Razin(1998),loc.cit.)。哺乳類において、DNAメチル化過程を触媒する既知の3つのDNAメチルトランスフェラーゼ(DNMT1、3a、及び3b)がある。各DNMTがCpGメチル化の維持、及び調節に寄与する対応分担は、明らかとされなければならないが、いまだ明らかではない。しかし、全3つの酵素は、明らかに胚形に必要不可欠であり、対応するノックアウトマウスは、生まれる前に、又は生後間もなく死に至る(Bestor,Hum.MoI.Genet.9(2000),2395−2402;El Osta,Bioessays 25(2003),1071−1084)。その間、DNAメチル化、クロマチン構造の一時的変異と、特定のヒストン一時的変異との関連は、数回見られる。DNAのメチル化は、ヒストン脱アセチル化、及びヒストンH3でのリジン9残基のメチル化と大部分関係がある(Sims,Trends Genet.19(2003),629−639,Fahrner,Cancer Res.62(2002),7213−7218)。従って、DNMTは、ヒストンアセチラーゼ(HDAC)又はコリプレッサー複合体と関連する。メチル基がどのようにCpG残基から除かれるのかもほとんどわかっていない。増殖細胞において、DNAメチル化は、おそらく複製の間にも受動的に生じ得るだろう。しかしながら、活性のある未知のデメチラーゼの存在により説明され得る有糸分裂細胞におけるDNA脱メチル化の例もある(Wolffe,Proc.Natl.Acad.Sd.96(1999),5894−5896)。
プロモーターのメチル化(しかし、非調節配列のものではない)は、安定、転写抑制と相互に関連する(Singal(1999),loc.cit.,Ng(2000),loc.cit.,Razin(1998),loc.cit.)。5−メチルシトシンの抑制特性は、2つの機構により影響され得る。第1に、DNAメチル化は、転写因子の結合を直接的に損なわせ得るというもの。第2に、抑制の最大部分に関与しそうな可能性は、メチル−CpG−結合タンパク質(MBP)の増大であるというものである(Ballestar,Eur.J.Biochem.268(2001),1−6)。MECP2又はMBD2(MeCP1複合体の構成要素)の如きMBPは、コリプレッサー複合体、及び抑制作用を有するHDACを伴い、そして転写因子に利用できない高密度クロマチン構造(ヘテロクロマチン)の形成に関与する(Ballestar(2001),loc.cit)。
腫瘍の形成が、遺伝子病変(例えば、突然変異又は転座)だけでなく、後成的変化によっても支持されることが明らかとなっている。異常なクロマチン構造又はDNAメチル化は、腫瘍遺伝子又は腫瘍抑制遺伝子の転写状態に影響を与え得、及び腫瘍の成長を促進し得る。当該DNAメチル化における変化は、正常なメチル化配列におけるメチル化の損失(低メチル化)、あるいは正常な非メチル化配列におけるメチル化(高メチル化)のいずれかを含む(Roberston(2000),Ioc.cit.,Herman,N.Engl.J.Med.349(2003),2042−2054;Momparler,Oncogene22(2003),6479−6483;Esteller,Science297(2002),1807−1808;Plass,Hum.Mol.Genet11(2002),2479− 488)。
広範囲のDNA低メチル化は、ほぼ全ての種類の腫瘍について記載される。腫瘍組織において、5−メチルシトシン含有量は、反復サテライト配列又は染色体のセントロメア領域に見られる脱メチル化事象の大部分を有する正常な組織と比較して、低減される。しかしながら、個々の場合、bcl-2又はc-mycの如き原がん遺伝子の脱メチル化、及び活性化もまた記載される(Costello,J.Med.Genet.38(2001),285−303)。
CpGアイランドは、通常、遺伝子調節機能に影響を及ぼす。これは、メチル化状態における変化が、関連する遺伝子座の転写活性における変化と主に直接的に関与することによる(Robertson(1999);Herman(2003);Esteller(2002);Momparler(2003);Plass(2002),all Ioc.cit。)。大抵のCpGアイランドは、正常細胞における非メチル化形態中に存在する。しかしながら、ある態様において、CpGアイランドは、遺伝子調節事象においてもメチル化され得る。例えば雌性細胞の非活性化X染色体のCpGアイランドの大部分は、メチル化される(Goto,Microbiol.Mol.Biol.Rev.62(1998),362−378)。CpGアイランドは、正常な老化作用の過程においてもメチル化され得る(Issa,Clin.Immunol.109(2003),103−108)。
がん(例えば突然変異)の遺伝的原因は不可逆的なものであるが、腫瘍形成に対する役割に寄与する後成的変化は可逆的となり得る。それ故、後成的変化の可能な処置は、新組織形成の治療のための新たな可能性を提示する(Herman(2003);Momparler(2003);Plass(2002),allloc.cit.;Leone,Clin.Immunol.109(2003),89−102;Claus,Oncogene 22 (2003), 6489−6496)。
ゲノムのCpGメチル化分析のための検出方法の開発は、CpGメチル化パターンにおける変化ががんの如き疾患に関連し得ることが見出される事実に起因する重要性を主に有している。現在のところ、主に、既知の遺伝子座のCpGメチル化の検出のために使用されることが知られている技術がある(Dahl,Biogerontology4(2003),233−250)。ゲノムを通じてCpGメチル化の分析を可能とする方法は、ほとんど確立されていない。以下に、適用の主要分野と共にCpGメチル化の分析のための最も一般的な方法を要約する。
特異的CpGジヌクレオチドのメチル化状態が、5−メチルシトシンに対する異なる感受性により特徴づけられる細菌の制限エンドヌクレアーゼのイソシゾマーを使用して、検出され得る。それらの例は、双方ともCCGG配列を切断する酵素HpaII、及びMspIであって、しかしながら、HpaIIは、内部シトシンがメチル化されない場合に限られる。いくつかのアッセイは、メチル化感受性制限酵素の使用に基づき、上記アッセイは、個々の遺伝子の分析、及び当該ゲノムを通じたCpGメチル化の分析の双方のために使用され得る。メチル化感受性制限消化の断片は、サザンブロット又は制限部位の側面に接する領域のゲノムPCRにより、主に検出される(Dahl(2003),loc.cit.)。現在までに刊行されている、ゲノムを通じたCpGメチル化の全分析法は、当該方法の構成成分として、メチル化感受性制限酵素を使用する。制限ランドマークゲノムスキャニング法(Restriction Landmark genomic Scanning、RLGS)(Costello,Methods27(2002),144−149)は、例えば、全次元が異なるメチル化感受性制限酵素で消化され2つのDNA母集団のCpGメチル化における相違を特定する、一種の2次元アガロースゲル電気泳動を使用する。メチル化CpGアイランド増幅法(Methylated CpG Island Amplification、MCA)は、メチル化SmaI制限部位を有する断片を充実させ、そして当該断片を増やすためにLM−PCRを使用する。かかる増幅産生物は、表示差異分析(Representational Difference Analyzis、RDA)(Smith,Genome Res.13(2003),558−569)又はCpGアイランドマイクロアレイ(Yan,Cancer Res.6(2001),8375−8380)を用いて、すでに成功裏に分析されている。
硫酸水素ナトリウムでの二本鎖ゲノムDNAの処理は、非メチル化シトシン残基の脱アミノ化を導きウラシル残基とし、及びもはや相補的ではない2つの一本鎖の形成を導く。この処理の間、5−メチルシトシンが維持される。このようにして形成された配列間の相違は、メチル化DNAと非メチル化DNAとの相違の根拠を作り出す(Frommer,Proc.Natl.Acad.Sci.889(1992),1827−1831)。亜硫酸水素塩で処理されたDNAは、ウラシル残基(以前は非メチル化シトシンであったもの)とチミジン残基がチミジンとして増幅され、5−メチルシトシン残基のみがシトシン残基として増幅されるPCRにおいて直接的に使用され得る。増幅に依存して、PDRに使用されるプライマーは、メチル化配列と非メチル化配列とを区別し、又はメチル化状態とは無関係に、断片を増幅する。例えば、非特徴的なプライマーを使用して増幅されるPCR断片は、直接的にシークエンスされ、メチル化、及び非メチル化CpGの占有率を決定し得る。
変性された一本鎖DNA内のCpGメチル化を認識する5-メチルシトシンに対する抗体は、主に個々の固定細胞の染色体上のCpGメチル化の免疫組織化学的染色のために使用される。しかし、これらの抗体は、豊富にメチル化された配列に適してはいない。
(a)配列番号1(図1)に示されるヌクレオチド配列を有する核酸配列;
(b)配列番号2(図1)に示されるアミノ酸配列を有するポリペプチドをコードするヌクレオチド配列を有する核酸配列;
(c)配列番号2(図1)に示されるアミノ酸配列を有するポリペプチドの断片をコードするヌクレオチド配列を有する核酸配列であって、ここで、該断片が該ポリペプチドの少なくともアミノ酸130〜361番を含み、メチル化DNAと結合し得る、前記核酸配列;
(d)(a)〜(c)のいずれか1つのポリヌクレオチドによりコードされるポリペプチドの変異体をコードするヌクレオチド配列を有する核酸配列であって、該変異体において1又は複数のアミノ酸残基が該ポリペプチドに比べて置換されており、該変異体がメチル化DNAと結合し得る、前記核酸配列;
(e)(a)〜(d)のいずれか1つの核酸配列とハイブリダイズし、かつ、(a)の核酸分子のヌクレオチド配列と少なくとも65%同一であって、メチル化DNAと結合し得るポリペプチドをコードするヌクレオチド配列を有する、核酸配列;
(f)メチル化DNAと結合し得る(b)の核酸分子によりコードされるポリペプチドと少なくとも65%同一であり、かつ、メチル化DNAと結合し得るポリペプチドをコードする、ヌクレオチド配列を有する核酸配列;および
(g)(a)〜(f)のいずれか1つのポリヌクレオチドのヌクレオチド配列と縮重しているヌクレオチド配列を有する核酸分子
またはかかるポリヌクレオチドの相補鎖からなる群から選択される、ヌクレオチド配列を含む。
(a)メチル化および/または非メチル化DNAを含むサンプルを本発明のポリペプチドと接触させること;および
(b)該ポリペプチドとメチル化DNAとの結合を検出すること
を含む方法に関する。
ヒトMBD2(Genbank受託番号NM003927;AA144〜230)のメチル−CpG結合ドメイン(MBD)に相当するcDNAを、プライマーMBD2−Nhe S(5’−AGA TGC TAG CAC GGA GAG CGG GAA GAG G−3’)(配列番号4)およびMBD2−Not AS(5’−ATC ACG CGG CCG CCA GAG GAT CGT TTC GCA GTC TC−3’)(配列番号5)並びにHerculaseDNAポリメラーゼ(Stratagene)を用い、逆転写ヒト一次マクロファージ全RNAからPCR増幅させた。サイクリングパラメーターは、95℃3分変性;95℃20秒、65℃20秒、72℃80秒の増幅34サイクル;72℃5分の最終伸張であった。このPCR産物を沈殿させ、NotI/NheIで消化し、Signal plg plusベクター(Ingenius,R&D Systems)のNotI/NheI部位にクローニングし、配列を確認し、plg/MBD2−Fc(真核細胞発現ベクター)を得た。ショウジョウバエS2細胞における組み換え発現のためのpMTBip/MBD2−Fcをクローニングするため、ヒトIgG1のFcテールと融合されたヒトMBD2のMBDを含むplg/MBD2−FcのApaI/NheI断片を、pMTBiP/V5−HisB(Invitrogen)のApaI/SpeI部位にサブクローニングした。
一本鎖のメチル化シトシンは、5−mC抗体を用いて効率的に検出され得るが、二本鎖DNA分子は検出されない。二本鎖CpGメチル化DNAの抗体様検出を可能にするため、上記実施例1に記載のベクターを、ヒトメチル−CpG結合ドメイン2(MBD2)のメチル−CpG結合ドメイン(MBD)、フレキシブルリンカーポリペプチドおよびヒトIgG1のFc部分を含む融合タンパク質をコードするように構築した。このタンパク質をショウジョウバエS2 Schneider細胞において金属誘導プロモーターの制御下で発現させ、Aタンパク質アフィニティークロマトグラフィーにより上清から回収した。この精製タンパク質は多量に発現され(4〜5mg/L細胞培養上清)、推定分子量は約40kDaであった(図2参照)。
ウエスタンブロット様の手順にて、MBD2−Fcが膜上でCpGメチル化DNAを検出できるかどうかを調べるため、本発明者らは、従来のサザンブロット法と同等であるが、ブロット前にDNAを変性させないキャピラリートランスファー系を用い、in vitroにてナイロン膜上に、種々のCpG濃度のメチル化または非メチル化PCR断片をブロットした。図3に示すように、標準的な免疫ブロット条件と一次抗体と等価なものとしてMBD−Fcを用い、メチル化DNAをナイロン膜上、一列に(図3A)、また、CpG含量に依存して(図3B)検出することができる。これらの結果は、MBD−Fc融合タンパク質が固相支持体に結合したCpGメチル化DNAを検出することができることを示す。
次のプロトコールは、スピンカラムを用いたCpGメチル化DNA断片の迅速富化を可能とする。このDNAは、Aタンパク質を介してセファロースビーズにカップリングされたMBD2−Fcタンパク質と結合している。メチル化DNAに対する親和性はメチル化CpG−ジヌクレオチドの密度と共に高くなり、洗浄するバッファーのイオン強度と共に低くなる。
1mlのTBS中、50μlのAタンパク質セファロース4ファーストフロービーズ(Amersham)に、8〜10μgの精製MBD2−Fcタンパク質を加え、4℃で一晩、回転装置上で回転させた。翌日、MBD2−Fc−ビーズをバッファーA(20mMのTris−HCl pH8.0、2mMのMgCl2、0.5mMのEDTA、150mMのNaCl、0.1%NP−40)で2回洗浄した。
少なくとも1μgのゲノムDNA(Qiagenカラムを用いて調製)をMseIで消化した。アガロースゲル電気泳動を用いて完全消化物を制御し、消化したDNAを、PicoGreen dsDNA定量試薬(Molecular Probes)を用いて正確に定量した。
消化したDNA(300ng)を1mlのバッファーA中の洗浄MBD2−Fc−ビーズに加え、4℃、回転装置上で3時間回転させた。ビーズをSpinXカラムに移し、およそ1mlのバッファーAで回転洗浄した。ビーズを400μlのバッファーB(20mMのTris−HCl pH8.0、2mMのMgCl2、0.5mMのEDTA、450mMのNaCl、0.1%NP−40)で2回、バッファーC(20mMのTris−HCl pH8.0、2mMのMgCl2、0.5mMのEDTA、650mMのNaCl、0.1%NP−40)で2回洗浄した。各洗浄ステップの流出液は廃棄するか、またはさらなる分析のために回収した。CpGメチル化DNAを、250μlバッファーD(20mMのTris−HCl pH8.0、2mMのMgCl2、0.5mMのEDTA、1000mMのNaCl、0.1%NP−40)で、新しい試験管中へ溶出した。溶出したDNAをQiaquickスピンカラム(溶出)で脱塩した。並行して、300ngの消化DNA(投入)を250μlのバッファーDに再懸濁させ、QIAquick PCR精製キット(Qiagen)を用いて脱塩した。溶出DNAおよび投入DNAの双方を、PicoGreen dsDNA定量試薬(Molecular Probes)を用いて正確に定量した。
DNAは種々の制限エンドヌクレアーゼを用いて、または音波処理によって制限処理してもよい。
MBD−Fc融合タンパク質が免疫沈降様のアプローチでCpGメチル化DNA断片と結合し得るかどうかを調べるため、本発明者らは、まず、in vitroで生成され、種々のメチル化を受けたDNA断片の結合特性を調べた。種々のCpG密度を有するヒトプロモーターのPCR断片を、PCRを用いて作製し(図4参照)、SssI(CCL13、TLR2、CHI3L1)を用いてCpGのメチル化を行うか、またはメチル化せずにおいた(CPM)。DNAを、150mMのNaCl中で、MBD−Fc−Aタンパク質セファロースビーズに結合させ(実施例4参照)、NaCl濃度を引き上げて溶出させた。画分を回収し、スピン精製し、アガロースゲル電気泳動を行った。
5.1.1
組み換えMBD−Fcタンパク質が、複合ゲノムDNA混合物中のCpGアイランドプロモーターのメチル化密度を検出できるかどうかを調べるため、3つの白血病細胞系統、正常ドナー単球、並びにAML患者の芽細胞由来のゲノムDNAをMseIで制限処理し、MCIpを行った。1000mMのNaCl MCIp画分中、3つのCpGアイランドプロモーター(TLR2、p15およびESR1)の富化を、LightCycler−PCRを用いて検出した。p15とESR1は白血病においてメチル化の既知の標的であり、また、TLR2はこれまでにU937細胞でメチル化され、THP−1細胞ではメチル化されないことが示されていることから、この3つの遺伝子座を選択した。
a.)低または高塩画分のいずれかで、低メチル化ゲノム断片より200〜300倍強い富化が見られる。
b.)低CpG密度の断片は高塩画分から主として排除される。
c.)分画MCIpアプローチはCpGメチル化密度における小さな違いを分解することができる{SssI処理単球DNAと非処理単球DNAの間の平均的な違いはメチル化CpG残基12のうちおよそ6個である(データは示されていない)}。
ゲノムDNAの複雑な混合物における単一遺伝子断片の検出に必要はDNAの量を決定するため、DNA断片の量を引き下げてMCIpおよびその後のLightCyclerリアルタイムPCRを行った。図6に示されるように、メチル化TLR2プロモーターはU937細胞由来のゲノムDNA 1ngといった少量から、富化および検出が可能である。非メチル化p15−プロモーターは、U937細胞においては有意には富化されなかった(20ng、MCIp溶出物)、または検出できなかった(4ngまたは1ng、MCIp溶出物)(図6)。これらの結果は、MCIpが、複雑なゲノム混合物においてメチル化DNA断片を検出するための高感度の方法であることを示す。
5.2.1
ライゲーション媒介(LM)−PCRを用いたゲノムMseI−断片由来のDNAアンプリコンの生成
MseI適合性LMPCR−リンカーを生成するため、オリゴヌクレオチドLMPCR S−L(5’−GCG GTG ACC CGG GAG ATC TCT TAA G−3’)(配列番号22)およびLMPCR AS−L(5’−TAC TTA AGA GAT C−3’)(配列番号23)を次のようにアニーリングした。両オリゴをヌクレアーゼフリーH2O(USB)中20μMの濃度で混合し、80℃で10分間インキュベートし、室温までゆっくり冷却した。アニーリングしたリンカーを50μlのアリコートとして−20℃で保存した。
単一遺伝子断片の富化を検出するため、MCIpアンプリコンを、PCR(LightCycler,標準的PCR)を用いて分析した。多重遺伝子断片を検出するため、アレイ技術を用い得る。例えばCpGアイランドマイクロアレイを用いたMCIpアンプリコンの分析は、MCIp−DNA断片の蛍光標識と、その後の標準的プロトコールを用いたマイクロアレイとのハイブリダイゼーションを含む。
この方法はELISAと類似のアプローチを用いる。CpGメチル化DNAに対して高親和性を有するタンパク質を、PCRサイクラー適合性反応容器の壁面にコーティングし、ゲノムDNA混合物から高メチル化DNA断片を選択的に捕捉するために使用する。特定のDNA断片(例えば、特定の遺伝子のCpGアイランドプロモーター)の保持は、同じ試験管でPCR(標準的PCRまたはリアルタイムPCR、単一または多重)を用いて検出することができる。メチル化の程度は、ゲノム投入DNAのPCR反応に対して評価することができる。図7は、MB−PCRの模式図を示す。
3つの細胞系統(KG1、U937、およびTHP−1)、正常ヒト単球(健康なドナー)およびAML患者の冷凍芽細胞からのゲノムDNAを、Blood and Cell Culture Midi Kit(Qiagen)を用いて調製した。このゲノムDNA調製物の質はアガロースゲル電気泳動により制御し、DNA濃度をUV分光光度法により測定した。ゲノムDNAをMse I(NEB)で消化し、最後に、PicoGreen dsDNA定量試薬(Molecular Probes)を用いて定量した。
MBD−FcコーティングPCR試験管を、熱安定性TopYield(商標)ストリップ(Nuncカタログ番号248909)を用いて調製した。50μlの組み換えMBD−Fcタンパク質(10mMのTris/HCl pH7.5中、15μg/mlに希釈)を各ウェルに加え、4℃で一晩インキュベートした。ウェルを200μlのTBS(150mMのNaClを含有する20mMのTris,pH7.4)で3回洗浄し、4℃で一晩、100μl遮断溶液(150mMのNaCl、4.5%スキムミルク粉末、5mMのEDTAおよび各0.8μg/mlのポリd(l/C)、ポリd(A/Tおよびポリd(CG)を含有する10mMのTris,pH7.5)で遮断した。試験管を200μlのTBST(0.1%Tween−20を含有するTBS)で3回洗浄した。
50μlの結合バッファー(400mMのNaCl、2mMのMgCI2、0.5mMのEDTA、および0.1%Tween−20を含有する20mMのTris,pH7.5)を各ウェルに加え、1μlのMseI消化DNA(10ng/μl)を各第2のウェルに加えた(M−反応)。ウェルを4℃で3時間、シェーカー上でインキュベートした。試験管を200μlの結合バッファーで3回、10mMのTris/HCl pH7.5で1回洗浄した。
TopYield(商標)ストリップで直接PCRを行った。PCR混合物(50μl/ウェルl)は、標準的なPCRバッファー(Roche)、2.5U FastStart TaqDNAポリメラーゼ(Roche)、各10pmolの遺伝子特異的プライマー(Qiagenにより合成)、dNTP(各200mM,Amersham/Pharmacia)、1Mベタイン(Sigma)を含み、プライマー配列およびサイクリングパラメーターはそれぞれ表2および3に示される。このPCR混合物を加えた後、1μlのMseI消化DNA(10ng/μl)を、事前にDNA断片と共にインキュベートしなかった各第2のウェルに加えた(P−反応)。PCR産物を、アガロースゲル電気泳動を用いて分析し、臭化エチジウムで染色したゲルを、Typhoon9200Imager(Amersham/Pharmacia)を用いて走査した。
Claims (21)
- メチル−CpG結合タンパク質(MBD)ファミリーに属するタンパク質のDNA結合ドメイン、及び抗体のFc部分を含む二機能性ポリペプチドをコードするヌクレオチド配列を有する、核酸分子。
- リンカーポリペプチドをコードするヌクレオチド配列をさらに含む、請求項1に記載の核酸分子。
- 前記メチル−CpG結合タンパク質(MBD)ファミリーに属するタンパク質のDNA結合ドメインが、MBD2タンパク質のDNA結合ドメインである、請求項1または2に記載の核酸分子。
- 以下の:
(a)配列番号1(図1)に示されるヌクレオチド配列を有する核酸分子;
(b)配列番号2(図1)に示されるアミノ酸配列を有するポリペプチドをコードするヌクレオチド配列を有する核酸分子;
(c)配列番号2(図1)に示されるアミノ酸配列を有するポリペプチドの断片をコードするヌクレオチド配列を有する核酸分子、ここで、該断片は、該ポリペプチドの少なくともアミノ酸130〜361番を含み、メチル化DNAと結合し得る;
(d)(a)〜(c)のいずれか1つのポリヌクレオチドによりコードされるポリペプチドの変異体をコードするヌクレオチド配列を有する核酸分子、ここで、該変異体において、1又は複数のアミノ酸残基は該ポリペプチドに比べて置換されており、該変異体はメチル化DNAと結合し得る;
(e)(a)〜(d)のいずれか1つの核酸分子とハイブリダイズし、かつ、(a)の核酸分子のヌクレオチド配列と少なくとも65%同一であって、メチル化DNAと結合し得るポリペプチドをコードするヌクレオチド配列を有する、核酸分子;
(f)メチル化DNAと結合し得る(b)の核酸分子によりコードされるポリペプチドと少なくとも65%同一であるポリペプチドをコードする、ヌクレオチド配列を有する核酸配列;および
(g)(a)〜(f)のいずれか1つのポリヌクレオチドのヌクレオチド配列と縮重しているヌクレオチド配列を有する核酸分子、
またはかかるポリヌクレオチドの相補鎖からなる群から選択されるヌクレオチド配列を含む、請求項1〜3のいずれか一項に記載の核酸分子。 - DNA、cDNA、ゲノムDNA、RNAまたはPNAである、請求項1〜4のいずれか一項に記載の核酸分子。
- 請求項1〜5のいずれか一項に記載の核酸分子を含む、ベクター。
- 前記核酸分子が、原核生物または真核生物宿主細胞における発現を可能とする発現制御配列と作動可能なように連結されている、請求項6に記載のベクター。
- 請求項1〜5のいずれか一項に記載の核酸分子、または請求項6若しくは7に記載のベクターで遺伝的に操作された、宿主細胞。
- メチル化DNAと結合し得るポリペプチドを産生する方法であって、請求項8に記載の宿主細胞を培養すること、および該ポリペプチドを回収することを含む、前記方法。
- メチル化DNAと結合し得るポリペプチドを発現し得る細胞を製造する方法であって、請求項6または7に記載のベクターで細胞をin vitroにおいて遺伝的に操作することを含む、前記方法。
- 請求項1〜5のいずれか一項に記載の核酸分子によりコードされるアミノ酸配列を有する、または請求項10の方法により得られる、ポリペプチド。
- 請求項11に記載のポリペプチドと特異的に結合する抗体。
- 請求項1〜5のいずれか一項に記載の核酸分子、請求項6または7に記載のベクター、請求項8に記載の宿主細胞、請求項11に記載のポリペプチド、または請求項12に記載の抗体を含む、組成物。
- 場合により好適な診断手段をさらに含む診断用組成物である、請求項13に記載の組成物。
- 場合により製薬上許容される担体をさらに含む医薬組成物である、請求項13に記載の組成物。
- in vitroでメチル化DNAを検出する方法であって、
(a)メチル化および/または非メチル化DNAを含むサンプルを請求項11に記載のポリペプチドと接触させること;および
(b)請求項11に記載のポリペプチドとメチル化DNAとの結合を検出すること
を含む方法。 - 逆サウスウエスタンブロット法、免疫沈降法、アフィニティー精製、メチル−CpG免疫沈降法(MCiP)またはメチル結合(MB−)PCR法である、請求項16に記載の方法。
- メチル化DNAを制限酵素消化、重亜硫酸塩シークエンシング、ピロシークエンシング、サザンブロット法またはPCRにより分析するステップ(c)をさらに含む、請求項16または17に記載の方法。
- メチル化DNAを検出するための、請求項11に記載のポリペプチド。
- メチル化DNAの検出を目的とした診断用組成物の製造のための、請求項1〜5のいずれか一項に記載の核酸分子、請求項6若しくは7に記載のベクター、請求項8に記載の宿主細胞、請求項11に記載のポリペプチド、または請求項12に記載の抗体の使用。
- 腫瘍組織または腫瘍細胞の検出を目的とした診断用組成物の製造のための、請求項1〜5のいずれか一項に記載の核酸分子、請求項6若しくは7に記載のベクター、請求項8に記載の宿主細胞、請求項11に記載のポリペプチド、または請求項12に記載の抗体の使用。
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JP5149013B2 (ja) | 2013-02-20 |
AU2005308918B2 (en) | 2012-09-27 |
AU2005308918A1 (en) | 2006-06-01 |
US9074013B2 (en) | 2015-07-07 |
EP1817430B1 (en) | 2009-09-16 |
US20210337252A1 (en) | 2021-10-28 |
EP1817430A2 (en) | 2007-08-15 |
JP2013027399A (ja) | 2013-02-07 |
DE602005016712D1 (de) | 2009-10-29 |
CA2589487C (en) | 2014-07-29 |
CN101243191B (zh) | 2014-04-16 |
CA2589487A1 (en) | 2006-06-01 |
CN101243191A (zh) | 2008-08-13 |
ATE443161T1 (de) | 2009-10-15 |
US20150267263A1 (en) | 2015-09-24 |
US9873919B2 (en) | 2018-01-23 |
WO2006056480A2 (en) | 2006-06-01 |
US20180220176A1 (en) | 2018-08-02 |
US20080260743A1 (en) | 2008-10-23 |
WO2006056480A3 (en) | 2008-03-27 |
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