JP6526612B2 - Talエフェクターに媒介されるdna修飾 - Google Patents
Talエフェクターに媒介されるdna修飾 Download PDFInfo
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- JP6526612B2 JP6526612B2 JP2016216110A JP2016216110A JP6526612B2 JP 6526612 B2 JP6526612 B2 JP 6526612B2 JP 2016216110 A JP2016216110 A JP 2016216110A JP 2016216110 A JP2016216110 A JP 2016216110A JP 6526612 B2 JP6526612 B2 JP 6526612B2
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Description
本出願は、すべてその全体で本明細書中に参考として組み込まれている、2009年12月10日に出願の米国仮出願第61/285,324号、2010年6月7日に出願の米国仮出願第61/352,108号、および2010年7月22日に出願の米国仮出願第61/366,685号の優先権を主張するものである。
本発明は、国立科学財団(National Science Foundation)によって授与された助成金第0820831号および第0504304号の下の政府支援で行った。政府が本発明の特定の権利を有する。
単離した核酸およびポリペプチドが本明細書中で提供されている。用語「核酸」および「ポリヌクレオチド」とは、互換性があるように使用され、cDNA、ゲノムDNA、合成(たとえば化学合成)DNA、および核酸類似体を含有するDNA(またはRNA)を含めた、RNAおよびDNAをどちらもいう。ポリヌクレオチドは任意の三次元構造を有することができる。核酸は二本鎖または一本鎖(すなわち、センス鎖またはアンチセンスの一本鎖)であることができる。ポリヌクレオチドの非限定的な例には、遺伝子、遺伝子断片、エクソン、イントロン、メッセンジャーRNA(mRNA)、トランスファーRNA、リボソームRNA、リボザイム、cDNA、組換えポリヌクレオチド、分枝状ポリヌクレオチド、プラスミド、ベクター、任意の配列の単離したDNA、任意の配列の単離したRNA、核酸プローブ、およびプライマー、ならびに核酸類似体が含まれる。
また、組換え核酸構築体(たとえばベクター)も本明細書中で提供されている。「ベクター」とは、それ内に別のDNAセグメントを挿入して、挿入したセグメントを複製させ得る、プラスミド、ファージ、またはコスミドなどのレプリコンである。一般に、ベクターは、適当な制御要素と会合している場合に複製が可能である。適切なベクター主鎖には、たとえば、プラスミド、ウイルス、人工染色体、BAC、YAC、またはPACなどの、当分野でルーチン的に使用されているものが含まれる。用語「ベクター」には、クローニングおよび発現ベクター、ならびにウイルスベクターおよび組込みベクターが含まれる。「発現ベクター」とは、1つまたは複数の発現制御配列が含まれるベクターであり、「発現制御配列」とは、別のDNA配列の転写および/または翻訳を制御および調節するDNA配列である。適切な発現ベクターには、それだけには限定されないが、たとえば、バクテリオファージ、バキュロウイルス、タバコモザイクウイルス、ヘルペスウイルス、サイトメガロウイルス、レトロウイルス、ワクシニアウイルス、アデノウイルス、およびアデノ関連ウイルスに由来するプラスミドおよびウイルスベクターが含まれる。数々のベクターおよび発現系がNovagen(ウィスコンシン州Madison)、Clontech(カリフォルニア州Palo Alto)、Stratagene(カリフォルニア州La Jolla)、およびInvitrogen/Life Technologies(カリフォルニア州Carlsbad)などの企業から市販されている。
配列特異的ヌクレアーゼおよび配列特異的エンドヌクレアーゼをコードしている組換え核酸が本明細書中で提供されている。配列特異的エンドヌクレアーゼには、TALエフェクターDNA結合ドメインおよびエンドヌクレアーゼドメインが含まれることができる。したがって、そのような配列特異的エンドヌクレアーゼをコードしている核酸には、ヌクレアーゼからのヌクレオチド配列と連結された配列特異的TALエフェクターからのヌクレオチド配列が含まれることができる。
また、ドナーヌクレオチド配列を含めた組換え核酸も、本明細書中で提供されている。ドナーヌクレオチド配列には、形質転換させる細胞のゲノム内に内在的に見つかる事前に選択された標的ヌクレオチド配列に関して1つまたは複数の修飾(すなわち、置換、欠失、または挿入)を有する変異体配列が含まれることができる(本明細書中で「修飾された標的ヌクレオチド配列」とも呼ばれる)。ドナー核酸内の変異体配列は、典型的には、両側が細胞内の内在標的ヌクレオチド配列と類似または同一の配列で隣接されている。隣接配列は任意の適切な長さを有することができ、典型的には、少なくとも50個のヌクレオチドの長さである(たとえば、少なくとも50個のヌクレオチド、少なくとも75個のヌクレオチド、少なくとも100個のヌクレオチド、少なくとも200個のヌクレオチド、少なくとも250個のヌクレオチド、少なくとも300個のヌクレオチド、少なくとも500個のヌクレオチド、少なくとも750個のヌクレオチド、少なくとも1000個のヌクレオチド、約50〜約5000個のヌクレオチド、約100〜2500個のヌクレオチド、約100〜約1000個のヌクレオチド、約100〜500個のヌクレオチド、約200〜約500個のヌクレオチド、または約250〜400個のヌクレオチド)。したがって、相同組換えは、生じる細胞のゲノムが、たとえば同じ遺伝子からの内在配列のコンテキスト内の変異体配列を含有するように、組換えドナー核酸構築体と変異体配列の両側の内在標的との間で起こることができる。ドナーヌクレオチド配列は、ゲノム内の任意の適切な配列を標的とするように作製することができる。たとえば、植物では、ドナーヌクレオチド配列は、脂質生合成遺伝子、炭水化物生合成遺伝子、種子貯蔵タンパク質遺伝子、疾患もしくは害虫耐性遺伝子、ストレス寛容遺伝子、乾燥寛容遺伝子、または抗栄養因子を産生する遺伝子を標的とすることができる。さらに、ドナーヌクレオチド配列は、本明細書中に記載の配列特異的ヌクレアーゼの認識部位を含有する。
本明細書中で提供されている方法の一部には、選択可能またはスクリーニング可能なマーカーをコードしている第3の組換え核酸の使用が含まれる。選択可能な特色をもたらすポリペプチドをコードしているヌクレオチド配列を、1つまたは複数の発現制御配列を含有する発現ベクター内に取り込ませることができる。たとえば、発現ベクターには、形質転換させる植物細胞中で構成的発現をもたらすプロモーター配列と作動可能に連結された選択マーカーをコードしている配列が含まれることができる。適切な選択マーカーには、それだけには限定されないが、カナマイシン、G418、ブレオマイシン、アンピシリン、もしくはハイグロマイシンなどの抗生物質、またはグルホシネート、クロロスルフロン(chlorosulfuron)、もしくはホスフィノスリシンなどの除草剤に対する耐性を与えるポリペプチドが含まれることができる。
本明細書中で提供されている構築体のうちの1つまたは複数を使用して、遺伝子改変した生物(たとえば植物または動物)が作製されるように、細胞を形質転換させることができるおよび/またはDNA修飾酵素を細胞内に導入することができる。したがって、本明細書中に記載の核酸および/またはポリペプチド(polypeptdes)を含有する遺伝子改変した生物および細胞も提供される。一部の実施形態では、形質転換細胞は、組換え核酸構築体がそのゲノム内に組み込まれている、すなわち安定に形質転換させることができる。安定に形質転換させた細胞は、典型的には、導入された核酸配列を各細胞分裂で保持する。構築体は、形質転換細胞に内在性のヌクレオチド配列が、内在配列に対応する配列を含有するが内在配列に関して1つまたは複数の修飾を含有する構築体によって置き換えられるように、相同的な様式で組み込まれることができる。そのような修飾された内在配列を含有する植物または動物は本明細書中で「遺伝子改変した生物」(GMO)と呼び得るが、修飾された内在配列は導入遺伝子とみなされないことに留意されたい。また、構築体は、形質転換細胞のゲノム内にランダムに組み込まれるように、非正統的な様式で組み込まれることもできる。
また、本発明は、たとえば、TALENをコードしている核酸分子、TALENポリペプチド、そのような核酸分子もしくはポリペプチドを含有する組成物、またはTALエンドヌクレアーゼを操作した細胞系を含有する製品も提供する。そのような物品は、たとえば、研究ツールとして、または治療的に使用することができる。
ポリペプチド配列中のアミノ酸残基またはサブユニットは、本明細書中で一文字のコードに従って命名されており、たとえば、QはGlnまたはグルタミン残基を意味し、RはArgまたはアルギニン残基を意味し、DはAspまたはアスパラギン酸残基を意味する。
TAL標的部位中のRVDと近接したヌクレオチドとの間に1対1の直線的な対応が存在するかどうかを決定するために、10個のTALエフェクターのそれぞれの既知の標的遺伝子の予測されたプロモーター領域(すなわち注釈付けされた翻訳開始部位の直前の1,000bp)を、TALエフェクターのRVD配列を用いて、RVD−ヌクレオチドの会合においてエントロピー(ランダム性)を最小限にしたアラインメントについて走査した。以下の式を使用してエントロピーを定量し、Rは、エフェクターのRVDの組であり、Dは、4個のヌクレオチド(A、C、G、T)の組であり、fi,jは、第i番目のRVDが第j番目のヌクレオチドと会合する観察された頻度を表す:
プラスミドの構築:TALエフェクター、AvrBs3のタンパク質コード配列は、プラスミドをBamHIで消化することから得られた。主に反復ドメインをコードしているDNA断片をSphIで切り出した。AvrBs3のアミノ酸配列はGENBANK受託番号P14727および配列番号12の下(図3)、核酸配列は受託番号X16130配列番号13の下(図4)で見つけることができる。図4中、BamHIおよびSphI部位は太字で下線が引かれている。AvrBs3のBamHIおよびSphI断片を、ヌクレアーゼ発現ベクターpDW1789_TAL(図5)内に、FokIヌクレアーゼドメインをコードしている配列に隣接してクローニングした。AvrBs3標的部位を標的レポータープラスミド内にクローニングするために、18bpのスペーサー配列をその間に含んで逆配向に配置された2つのAvrBs3認識部位を含有する2つの相補的DNAオリゴを、5’および3’末端でそれぞれBglIIおよびSpeIのオーバーハングを有するように合成した。6、9、12および15bpのスペーサー長を用いて、認識部位を有する他のレポータープラスミドを作製した。アニーリングさせたDNAオリゴをレポータープラスミドpCP5内にクローニングし(図6)、これをBglIIおよびSpeIで消化した。
それぞれが異なるヌクレオチドを指定する4つの個々のTALエフェクター反復のそれぞれの、102個の塩基対に対応する相補的オリゴヌクレオチドを合成し、アニーリングし、個々にならびにすべての順列の2回および3回の反復の組合せで高コピーの細菌クローニングベクター内にクローニングして、標準の制限消化およびライゲーション技法を使用して4個の単一、16個の二重、および64個の三重反復モジュールを得た(たとえば図11に例示)。所望のTALエフェクターのコード配列は、適切なモジュールを、特徴的な最後の半反復以外の中央反復領域を欠くtal1c遺伝子の切断された形態を含有するGateway−ready高コピー細菌クローニングベクター内に順次導入することによってアセンブルする。たとえば、18回反復のTALエフェクターのコード配列は、5個の三重モジュールおよび1個の二重モジュールを切断されたtal1cベクター内に順次導入することによってアセンブルすることができる。
誂えのTALエフェクターをコードしている遺伝子を作製するためのプラスミドおよび方法を開発した。本明細書中に記載のように、TALエフェクターの機能的特異性は反復中のRVDによって決定され、反復およびタンパク質中の他の箇所中の他の多型は稀であり、機能的特異性に関して重要でない。したがって、自由裁量によるTALエフェクター遺伝子の反復領域を所望のRVDを含有する反復で置き換えることによって、誂えのTALエフェクター遺伝子を作製した。RVDの外の反復配列はコンセンサス配列に一致した(以下を参照)。TALエフェクター反復をコードしているDNA断片を、1回、2回、または3回の反復をコードしているモジュール内に順次アセンブルし、元の反復が除去されたTALエフェクター遺伝子内にモジュールをクローニングした。最後の(半)反復を例外として、それぞれのコードされている反復は、配列LTPDQVVAIASXXGGKQALETVQRLLPVLCQDHGを有していた(配列番号18、図12A)。最後の(半)反復は配列LTPDQVVAIASXXGGKQALESを有していた(配列番号20、図12B)。どちらの配列でも、「XX」はRVDの位置を示す。モジュール反復中で使用したRVDは、それぞれA、C、G、およびTとの結合を指定するNI、HD、NN、およびNGであった。以下に記載の実験では、その反復が除去されたXanthomonas oryzae pv.oryzicola株BLS256のtal1c遺伝子を、誂えのTALエフェクター遺伝子を構築するための「主鎖」として使用した。
(1)第1の所望の反復を有する単一反復の開始プラスミド(それぞれRVD NI、HD、NN、またはNGをコードしているpCS493、pCS494、pCS495、またはpCS495)を選択するステップ、
(2)プラスミドをPspXIで直鎖状にするステップ、
(3)XhoIを使用して次の反復(複数可)のモジュールを適切なモジュールプラスミド(pCS502〜pCS585)から単離するステップ、
(4)ライゲーションするステップ、
(5)MscIで消化することによって配向を確認し、ベクターに基づくプライマーを使用して配列を3’末端から確認するステップ、および
(6)すべての反復がアセンブルされるまでステップ2〜5を繰り返すステップ。
本明細書中に記載のTALEN反復のアセンブリ(たとえば図20に示したステップを使用)は、増加していく数の反復を含有する数々の中間体プラスミドをもたらす。これらのプラスミドのそれぞれは、TALENのモジュールアセンブリ用プラスミド(pMAT)のライブラリが作製されるように保管されている。たとえば、図21Aおよび21Bは、示されているヌクレオチド配列を標的とするTALエンドヌクレアーゼの構築における反復モジュールのアセンブリを示す。図21Aでは、pCS519、pCS524、pCS537、pCS551、pCS583、およびpCS529と命名されたプラスミドからの反復モジュールを、pCS493と命名された開始プラスミド中の配列に順次付加して、pMAT55、pMAT56、pMAT57、pMAT58、pMAT59、およびpMAT60と命名されたプラスミドがもたらされる。図21Bでは、pCS530、pCS533、pCS522、およびpCS541と命名されたプラスミドからの反復モジュールを、pMAT1と命名されたプラスミド中の配列に順次付加して、pMAT61、pMAT62、pMAT63、およびpMAT64と命名されたプラスミドがもたらされる。
実施例4および5に記載のシステムを使用して、TALのDNA認識ドメインを使用して特定のDNA標的を認識および切断するTALENを作製した(図22A)。TALENの機能を評価するために、LacZ活性がDNA切断の指標として役割を果たす酵母アッセイを適応させた(Townsendら、上記)。このアッセイでは、標的プラスミドおよびTALEN発現プラスミドを接合によって同じ細胞中で一緒にした。標的プラスミドは、コード配列の125bpの重複を有するlacZレポーター遺伝子有する。重複は、所定のTALENによって認識される標的部位に隣接する。二本鎖DNAの切断が標的部位で起こる際、これが重複した配列間の一本鎖のアニーリングによって修復され、それにより、機能的なlacZ遺伝子が作製され、その発現は定量可能な読取値を提供する標準のβ−ガラクトシダーゼアッセイによって測定することができる(図22A)。このアッセイは、NHEJによって染色体の突然変異を生じる、または高等真核生物において遺伝子編集のために相同組換えを刺激する、ZFNの能力の良好な予測子であることが実証されている(Townsendら、上記、およびZhangら(2010)Proc.Natl.Acad.Sci.USA、107:12028〜12033)。
MoscouおよびBogdanove(上記)によって分析した20個の対合した標的およびTALエフェクターを、全体的な組成の偏りおよびヌクレオチドまたはRVD頻度に対する位置効果について評価した。部位(プラス鎖上)は一般にAおよびCに富み、Gに乏しいことが観察された。平均パーセントAは31±16%であった(1単位の標準偏差)。平均パーセントCは37±13%であった。平均パーセントGは9±8%であり、平均パーセントTは22±10%であった。アラインメントは長さが変動するため、位置効果の分析はそれぞれの末端上の5個の位置に限定された。驚くべきことに、位置1および3でAが有利およびTが不利であり、位置Nおよび場合によっては位置2でTが有利である、標的配列中の偏りが明らかであった。Gは位置N−1で特に稀であった。この偏りはエフェクター中の一致するRVDによって反映されており、位置1および3にはNIが最も一般的であり、位置1にはNGが存在せず、位置Nにはほぼ必ずNGが存在し、位置N−1にはNNは稀である(図30)。
Golden Gateクローニング方法[Englerら(2008)、上記、およびEnglerら(2009)、上記]は、その認識部位の外側で切断して、複数のDNA断片を同時に規則的にライゲーションさせるための誂えのオーバーハングを作製する、IIS型制限エンドヌクレアーゼ(たとえばBsaI)の能力を用いる。この方法を使用して、単一の反応で、いくつかのDNA断片を特定の順序でアレイへと融合させ、所望のデスティネーションベクター(destination vector)内にクローニングすることができる(図31)。
実施例6は、ユニークなDNA配列を認識できるようにTALENのDNA結合ドメインを操作するために実施した実験を記載している。記載のように、これらの誂えのTALENは、シロイヌナズナADH1およびゼブラフィッシュgridlock遺伝子中の部位を認識した。これらの遺伝子だけでなく、シロイヌナズナからのTT4遺伝子、およびゼブラフィッシュからのテロメラーゼ中の部位を認識するように、追加の誂えのTALエフェクターDNA結合ドメインを操作した(Foleyら、上記、およびZhangら、上記)。これらの誂えのTALENは、実施例3、4および8に記載の方法を使用して作製した。誂えのTALENの操作において、観察された組成的および位置的な偏りは、設計原理または「規則」として適応した。最初に、5’のTによって先行されており、少なくとも15bpの長さであり、上述の平均と一貫性のあるヌクレオチド組成を有するコード領域中の配列の検索を実施した。具体的には、0〜63%のA、11〜63%のC、0〜25%のG、および2〜42%のTを有する部位のみを選択した。そのような部位は平均して7〜9bpごとに存在した。その後、上述の観察された位置的な偏りに順応した部位を選択した。操作したTALENの結合によりFokIの二量体化が可能となるように、この組から、15〜19bpの長さであり、15〜18bpによって分離されている、それぞれの遺伝子中の結合部位の2つの対を同定した。モジュールアセンブリ方法(実施例3および4)は、部分的な長さの構築体を生じた。
実施例2、6および9のデータは、新規標的DNA配列を認識するように誂えのTALENを操作できることを実証している。ホモ二量体標的部位を認識した個々のTALEN単量体を使用して、誂えのTALENの酵母活性データを集めた。すなわち、TALENの標的配列を15〜18bpのスペーサー両側に逆の配向で重複させた。しかし、内在染色体配列の切断は、一般に、2つの異なる誂えのTALENがスペーサーの両側の2つの異なる配列を認識することを必要とする。実施例6に記載のように、この能力は、一緒にしたAvrBs3およびPthXo1 TALENについて、酵母アッセイにおいて、対応するキメラ標的部位を使用して実証した。本発明者らは、2つの異なる誂えのTALENが天然に存在するDNA配列を認識および切断することができるかどうかを試験した。実施例2に記載の酵母アッセイを使用して、シロイヌナズナADH1遺伝子中の2つの異なる標的配列を切断するように設計された誂えのTALENを、これらの標的に対する活性についてアッセイした。標的部位および対応するTALENのDNA配列は図36Aに示されている。TALENのアミノ酸配列は図34に提供されている。酵母アッセイで得られたベータ−ガラクトシダーゼ活性は、図36Bに示されているグラフ中にプロットされている。TALENのその天然に存在する標的配列に対する活性は陰性対照よりも有意に高く、これは、内在標的DNA配列を認識および切断するためにTALENを設計できることを示している。
シロイヌナズナADH1遺伝子中の標的配列を認識するように設計された活性TALEN対のうちの1つを、染色体DNAを結合、切断および突然変異させることができるかどうかを決定するために試験した。この対(pTALEN69および74)を含む個々のADH1 TALENのそれぞれを、TALENを構成的な35Sプロモーターの制御下に置く植物発現ベクターpFZ14内にクローニングした(Zhangら、上記)。その後、生じる構築体を、シロイヌナズナのプロトプラスト内に電気穿孔によって導入した。48時間後、ゲノムDNAを単離し、Tth111lで消化した。Tth111l切断部位は2つのTALEN認識部位の間のスペーサー配列中に位置する(図37A)。TALENによる染色体DNAの切断は、不正確な非相同末端結合(NHEJ)によって突然変異を導入することが予想され、これはTth111lによる切断の失敗をもたらす。その後、TALEN認識部位を包含する375bpの断片をPCR増幅した。PCR産物を再度Tth111lで消化して、TALENに媒介されるNHEJによって改変されなかった残りのゲノムDNAのほとんどを除去する。その後、消化産物をアガロースゲル上に流す。未切断のPCR産物が観察され、そのような未切断のPCR産物は、内在標的配列でのヌクレアーゼ活性(この事例ではTALEN活性)の指標である(Zhangら、上記)。未切断のDNAをクローニングし、DNA配列決定によって分析した。9個の独立したクローンの配列決定により、6個がNHEJによって導入された突然変異を保有していたことが明らかとなった(図37B)。したがって、TALENは、内在染色体座位を切断し、DNA二本鎖切断および突然変異を導入する。
TALエフェクターDNA暗号の中核では、4つの最も一般的なRVDは、会合頻度に基づいて4個のヌクレオチドに対して見かけ上1対1の特異性を有する。これは、HD、NG、およびNIで顕著にそうであるが、NNではその度合がより低い(図1C)。NNは最も頻繁にはGと会合するが、ほぼ同じように一般的にAと、時折CまたはTと会合する。13個のRVD配列中の4つの位置にNNを有するランダムにアセンブルされたTALエフェクターでは、人工標的中のすべての対応する位置にGを持つことで最良の活性が得られた(Bochら(2009)Science、326:1509〜1512)。Aは活性を減少させたが消失させず、CおよびTは検出可能な活性を排除した。NNである24個のRVDのエフェクターPthXo1の結合部位中の第1位置のみでGをC、T、またはAで置換した場合に、活性の劇的な損失が観察された(Romerら(2010)New Phytol.、187:1048〜1057)。しかし、これは、はるかにより短いAvrHah1(14個のRVD)がAとアラインメントするNNで始まり、23個のRVDのエフェクターPthXo6が位置4〜6にそれぞれAとアラインメントするNNを連続して3個有するが、これらのタンパク質はどちらの活性が高いという観察と対照的であった(Schornackら(2008)New Phytol.、179:546〜556、およびRomerら、上記を参照)。したがって、Gに対するNNの特異性は一般に弱いと考えられ、コンテキストに伴って変動する場合がある。
表1Aおよび1Bに記載されたRVDをRVD中の第2アミノ酸残基(すなわち、全体的な反復中の13番目)によって群分けした場合に、RVDの第1位置のアミノ酸とは無関係に、そのアミノ酸とRVDによって指定されるヌクレオチド(複数可)とのほぼ完璧な相関が存在したことが観察された(表7)。したがって、ギャップ(星印によって示す)で終わるRVDはCもしくはT、またはTを指定し、Dで終わるRVDはCを指定し、Gで終わるRVDはTを指定し、Nで終わるRVDはGもしくはA、またはGを指定する。また、RVDの位置1のアミノ酸はH、I、N、S、またはYのいずれかであったことも観察された。これらの観察は、RVDの特異性は、第1位置の残基がH、I、N、S、またはYであるかに依存せずに、第2位置の残基によって決定されることを示唆した。したがって、第2位置で観察された残基を第1位置の残基H、I、S、N、またはYと組み合わせるいくつかの新規(すなわち未だ観察されていない)RVDについて、特異性を予測した。したがって、I*、S*、およびY*はCもしくはT、またはTを指定すると予測され、ID、SD、およびYDはCを指定すると予測され、SGはTを指定すると予測され、INおよびYNはGもしくはA、またはGを指定すると予測された。また、第2位置のKは1つの事例しかなかったが、観察されたNKの特異性に基づいて、HK、IK、SK、およびYKはGを指定すると予測された。
TALENを動物細胞における標的化突然変異誘発に使用できるかどうかを試験するために、最初に、TALエフェクターAvrBs3、PthXo1、およびTal1cの発現をヒト胚性腎臓(HEK)293T細胞中で試験した。AvrBs3、PthXo1、およびTal1cをコードしている遺伝子からストップコドンを除去し、遺伝子を、哺乳動物発現ベクターpcDNA3.2/V5−DEST(Invitrogen、カリフォルニア州Carlsbad)内に、タンパク質の免疫検出のためのV5エピトープをコードしているそのベクター中の下流配列とインフレームでサブクローニングした。pcDNA3.2/V5−DESTは、TALエフェクター遺伝子を構成的ヒトサイトメガロウイルス(CMV)プロモーターの制御下に置く。生じるプラスミドを個々に用いて、Lipofectamine 2000(Invitrogen)を使用してHEK293T細胞を形質移入し、24時間後、全タンパク質をそれぞれの形質移入した細胞のバッチから単離し、ポリアクリルアミドゲル電気泳動、ウエスタンブロッティングおよびマウス抗V5抗体を使用した免疫標識に供した。標識されたタンパク質は、ヤギ抗マウス抗体−西洋ワサビペルオキシダーゼのコンジュゲートを用いて、SuperSignal Weat Pico化学発光キット(ThermoScientific,Inc.)を使用して検出した。等価なローディングは、アクチンの免疫標識および検出によって確認した。それぞれのTALエフェクタータンパク質は、明らかな分解なしに、検出可能に発現された(図39)。
本発明をその詳細な説明と併せて記載したが、前述の説明は、添付の特許請求の範囲によって定義される本発明の範囲を例示し、限定しないことを意図することを理解されたい。他の態様、利点、および改変が以下の特許請求の範囲内にある。
Claims (25)
- 細胞の遺伝物質をin vitroで修飾する方法であって、
(a)標的DNA配列を含有する細胞を提供するステップと、
(b)転写活性化因子様(TAL)エフェクターエンドヌクレアーゼをコードするベクターを前記細胞へ導入するステップであって、
前記TALエフェクターエンドヌクレアーゼは、
(i)二本鎖DNAを切断することができるエンドヌクレアーゼドメイン、ここで、前記エンドヌクレアーゼドメインはII型制限エンドヌクレアーゼに由来し、前記II型制限エンドヌクレアーゼはFokIである、および
(ii)組み合わせで標的DNA配列中の特定のヌクレオチド配列と結合する複数のTALエフェクター反復配列を含むTALエフェクタードメイン
を含むものであり、
前記TALエフェクターエンドヌクレアーゼが、前記細胞中の前記特定のヌクレオチド配列内にあるまたはそれに隣接する前記標的DNA配列を切断するように、TALエフェクターエンドヌクレアーゼを前記細胞へ導入する、ステップと
を含む、方法。 - 請求項1に記載の方法であって、
前記標的DNA配列の少なくとも一部分に相同的な配列を含む核酸を、前記標的DNA配列と前記核酸との間で相同組換えが起こるように、前記細胞に提供するステップをさらに含む、方法。 - 前記細胞が哺乳動物細胞である、請求項1または2に記載の方法。
- 前記細胞が植物細胞である、請求項1または2に記載の方法。
- 請求項1〜4のいずれか1項に記載の方法であって、
前記導入ステップが、前記TALエフェクターエンドヌクレアーゼをコードしているベクターを用いて細胞を形質移入することを含む、方法。 - 請求項1〜5のいずれか1項に記載の方法であって、
前記標的DNA内の特定のヌクレオチド配列と結合する前記TALエフェクタードメインが、15以上のTALエフェクター反復配列を含む、方法。 - 請求項6に記載の方法であって、
それぞれのTALエフェクター反復配列が、前記標的DNA配列中の塩基対の認識を決定する反復可変性二残基(RVD)を含み、
それぞれのTALエフェクター反復配列が、前記標的DNA配列中の1つの塩基対の認識を司っており、
前記RVDが、
Cを認識するためのHD、
Tを認識するためのNG、
Aを認識するためのNI、
Gを認識するためのNN、
Aを認識するためのNS、
Tを認識するためのHG、
Tを認識するためのIG、
Gを認識するためのNK、
Cを認識するためのHA、
Cを認識するためのND、
Cを認識するためのHI、
Gを認識するためのHN、および
Gを認識するためのNA、
のうちの1つまたは複数を含む、方法。 - TALエフェクターエンドヌクレアーゼをコードしている核酸を作製する方法であって、前記方法は、
(a)細胞のゲノム中の第1のユニークなヌクレオチド配列を同定するステップと、
(b)(i)組み合わせで前記第1のユニークなヌクレオチド配列と結合する複数のTALエフェクター反復配列、および(ii)第1のヌクレオチド配列内にあるまたはそれに隣接する二本鎖切断を生じるエンドヌクレアーゼを含む、TALエフェクターエンドヌクレアーゼをコードしている核酸を合成するステップであって、
前記エンドヌクレアーゼは、FokIであり、
それぞれのTALエフェクター反復配列が、前記標的DNA中の塩基対の認識を決定するRVDを含み、
それぞれのTALエフェクター反復配列が、前記標的DNA中の1つの塩基対の認識を司っており、
前記TALエフェクターエンドヌクレアーゼが、以下のRVD:
Cを認識するためのHD、
Tを認識するためのNG、
Aを認識するためのNI、
Gを認識するためのNN、
Aを認識するためのNS、
Tを認識するためのHG、
Tを認識するためのIG、
Gを認識するためのNK、
Cを認識するためのHA、
Cを認識するためのND、
Cを認識するためのHI、
Gを認識するためのHN、および
Gを認識するためのNA、
のうちの1つまたは複数を含む
ステップと
を含む、方法。 - 請求項8に記載の方法であって、
前記第1のヌクレオチド配列が、最小で15個の塩基の長さであり、5’から3’に配向されており、Tが5’末端の部位の直前にある、方法。 - 請求項8に記載の方法であって、
前記細胞のゲノム中の第2のヌクレオチド配列を同定するステップをさらに含み、
前記第1および第2のヌクレオチド配列が、18bpで分離されている、方法。 - 前記エンドヌクレアーゼが、前記第1および第2のヌクレオチド配列の間に二本鎖切断を生じる、請求項8または10に記載の方法。
- エンドヌクレアーゼドメインと標的DNAに特異的なTALエフェクターDNA結合ドメインとを含む単量体TALエフェクターエンドヌクレアーゼであって、
前記エンドヌクレアーゼドメインはII型制限エンドヌクレアーゼに由来し、ここで、前記II型制限エンドヌクレアーゼは、FokIであり、
前記DNA結合ドメインが複数のTALエフェクター反復配列を含み、
それぞれのTALエフェクター反復配列が前記標的DNA中の塩基対の認識を決定するRVDを含み、
それぞれのTALエフェクター反復配列が、前記標的DNA中の1つの塩基対の認識を司っている、単量体TALエフェクターエンドヌクレアーゼ。 - 前記単量体が、スペーサーを含む二連認識部位にわたって、別の単量体とのダイマーとして機能し、FokIを二量体化させて、前記スペーサー内の前記標的DNA内に二本鎖切断を生じる、請求項12に記載の単量体TALエフェクターエンドヌクレアーゼ。
- 請求項12に記載の単量体TALエフェクターエンドヌクレアーゼであって、
前記単量体TALエフェクターエンドヌクレアーゼが、以下のRVD:
Cを認識するためのHD、
Tを認識するためのNG、
Aを認識するためのNI、
Gを認識するためのNN、
Aを認識するためのNS、
Tを認識するためのHG、
Tを認識するためのIG、
Gを認識するためのNK、
Cを認識するためのHA、
Cを認識するためのND、
Cを認識するためのHI、
Gを認識するためのHN、および
Gを認識するためのNA、
のうちの1つまたは複数を含む
単量体TALエフェクターエンドヌクレアーゼ。 - 非ヒト動物を作製する方法であって、
i)遺伝子修飾を導入することが所望される標的DNA配列を含む真核細胞を提供するステップであって、前記細胞は請求項12〜14のいずれか1項に記載のTALエフェクターエンドヌクレアーゼをコードする核酸を含む、ステップと、
ii)TALエフェクターエンドヌクレアーゼを用いて、前記標的DNA配列内で二本鎖切断を生じるステップと、
二本鎖切断が起こった細胞から非ヒト動物を作製するステップとを含む、方法。 - 請求項15に記載の方法であって、
前記標的DNAの少なくとも一部分に相同的な配列を含む外因性核酸を、前記細胞内に導入するステップであって、
前記導入するステップが、前記外因性核酸と前記細胞またはその子孫中の前記標的DNA配列との間に相同組換えが起こることを可能にする条件下で行われる、ステップと、
相同組換えが起こった細胞またはその子孫から非ヒト動物を作製するステップと
をさらに含む、方法。 - 植物を作製する方法であって、
i)事前に選択された遺伝子修飾の導入が所望される標的DNA配列を含む植物細胞を提供するステップであって、前記植物細胞は請求項12〜14のいずれか1項に記載のTALエフェクターエンドヌクレアーゼをコードする核酸を含む、ステップと、
ii)TALエフェクターエンドヌクレアーゼを用いて、前記標的DNA配列内に二本鎖切断を生じるステップ
と、
iii)二本鎖切断が起こった細胞またはその子孫から植物を作製するステップと
を含む、方法。 - 請求項17に記載の方法であって、
前記標的DNA配列の少なくとも一部分に相同的な配列を含む外因性核酸を、前記植物細胞内に導入するステップであって、前記導入するステップが、前記外因性核酸と前記細胞またはその子孫中の前記標的DNA配列との間で相同組換えが起こることを可能にする条件下で行われる、ステップと、
相同組換えが起こった細胞またはその子孫から植物を作製するステップと
をさらに含む、方法。 - 細胞におけるin vitroでの標的化遺伝子組換えの方法であって、
i)請求項12〜14のいずれか1項に記載のTALエフェクターエンドヌクレアーゼをコードしている核酸を前記細胞内に導入するステップであって、前記TALエフェクターエンドヌクレアーゼは選択されたDNA標的配列を標的とする、ステップと、
ii)前記細胞内での前記TALエフェクターエンドヌクレアーゼの発現を誘導するステップと、
iii)前記選択されたDNA標的配列が突然変異を示している細胞を同定するステップと
を含む、方法。 - 前記突然変異が、遺伝物質の欠失、遺伝物質の挿入、ならびに遺伝物質の欠失および挿入の両方からなる群から選択される、請求項19に記載の方法。
- 前記細胞内にドナーDNAを導入するステップをさらに含む、請求項19に記載の方法。
- 前記細胞が昆虫細胞、植物細胞、魚細胞、または哺乳動物細胞である、請求項19〜21のいずれか1項に記載の方法。
- 核酸であって、
(i)二本鎖DNAを切断することができるエンドヌクレアーゼドメイン、ここで、前記エンドヌクレアーゼドメインはII型制限エンドヌクレアーゼに由来し、前記II型制限エンドヌクレアーゼはFokIである、および
(ii)組み合わせで選択された標的DNA配列と結合する、複数のTALエフェクター反復配列を含むTALエフェクタードメイン、
を含むTALエフェクターエンドヌクレアーゼをコードする、
核酸。 - 請求項23に記載の核酸と作動可能に連結されたプロモーターを含む発現カセット。
- 請求項24に記載の発現カセットを含む宿主細胞。
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