KR20190115717A - 동물 세포에서 표적 dna의 메틸화 감소와 표적 유전자의 발현 증가를 위한 조성물, 키트, 및 이를 이용한 방법 - Google Patents
동물 세포에서 표적 dna의 메틸화 감소와 표적 유전자의 발현 증가를 위한 조성물, 키트, 및 이를 이용한 방법Info
- Publication number
- KR20190115717A KR20190115717A KR1020180038740A KR20180038740A KR20190115717A KR 20190115717 A KR20190115717 A KR 20190115717A KR 1020180038740 A KR1020180038740 A KR 1020180038740A KR 20180038740 A KR20180038740 A KR 20180038740A KR 20190115717 A KR20190115717 A KR 20190115717A
- Authority
- KR
- South Korea
- Prior art keywords
- leu
- ser
- glu
- pro
- arg
- Prior art date
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Abstract
일 양상에 따른 동물 세포에서 표적 DNA의 메틸화를 감소시키기 위한 조성물, 키트, 및 이를 이용한 동물 세포에서 표적 DNA를 탈메틸화시키는 방법을 제공한다. 이에 따르면, DME에 의해 표적 DNA에 특이적으로 탈메틸화를 유도하여 표적 유전자의 발현을 특이적으로 유도할 수 있다. 또한, 기존의 5-아자시티딘이나 데시타빈 처리에 의한 비특이적 수동적 DNA 탈메틸화 기술을 대체할 수 있고, 임상적인 측면에서 표적 특이적 후성유전학적 치료 방법에 활용할 수 있다.
Description
동물 세포에서 표적 DNA의 메틸화를 감소시키기 위한 조성물, 키트, 및 이를 이용하여 동물 세포에서 표적 DNA의 메틸화를 감소시키는 방법에 관한 것이다.
DNA 메틸화(mehtylation)는 염색질 구조 및 유전자 발현을 조절하는 주요 후성유전학적(epigenetic) 기작의 하나이다. 일반적으로, DNA 과메틸화(hypermethylation)에 의해 염색질이 응축되고 유전자의 발현이 억제되고, DNA 탈메틸화(demethylation)에 의해 염색질의 응축이 풀어지고 유전자의 발현이 유도된다.
진핵생물에서 DNA 메틸화는 일반적으로 DNA 염기 중 하나인 시토신(cytosine)의 5-메틸시토신(5-methylcytosine: 5mC)으로의 변환을 의미하며, DNA 메틸화효소(DNA methyltransfrase: DNMT)에 의해 이루어진다. DNA 탈메틸화는 5-메틸시토신의 시토신으로 변환을 말하고, 수동적 또는 능동적 탈메틸화가 일어난다. 동물에서 능동적 탈메틸화는 DNA 수산화효소(hydroxylase)인 TET(Ten-Eleven Translocation) 단백질에 의해 5mC이 산화되어 5-히드록시메틸시토신(5-hydoxymethylcytosine: 5hmC)으로 변환되고, 순차적으로 5-포르밀시토신(5-formylcytosine: 5fC) 및 5-카르복실시토신(5-carboxylcytosine: 5caC)으로 변형되고, 이후 티민 글리코실라제와 같은 미스매치 글리코실라제에 의해 제거된다. 식물에서 능동적 5mC의 탈메틸화는 DNA 글리코실라제(glycosylase)인 DEMETER가 DNA에서 5mC를 직접적으로 제거하고 염기 절제 수선(base excision repair)을 통해 시토신으로 변환시킬 수 있다(Choi et al., Cell, vol.110, pp.33-42, July 12, 2002). 식물의 DME 유전자군은 지금까지 진핵생물에서 직접적으로 5mC를 제거할 수 있는 유일한 활성을 갖는 단백질을 암호화하는 것으로 알려져 있다.
사람의 경우, 비정상적인 DNA 메틸화는 암을 포함한 주요 질병의 원인으로 작용하는 것으로 알려져 있다. 비정상적인 DNA 메틸화를 감소시키는 후생유전학적 항암 치료 방법으로서, 5-아자시티딘(azacytidine, Vidaza®), 5-아자-2'-데옥시시티딘(Decitabine, Dacogen®) 등 DNMT를 불활성화 시키는 저해제를 처리하여 수동적 DNA 탈메틸화를 유도하는 방법이 사용되어 왔다. 그러나, Vidaza나 Dacogen의 사용은 흔히 적혈구, 백혈구 및 혈소판의 감소에 의한 빈혈, 감염, 출혈 등의 심각한 부작용을 초래한다. 이러한 부작용의 원인은 게놈 전체의 비선택적 DNA 탈메틸화를 유도하기 때문에 정상적으로 메틸화된 유전자도 동시에 영향을 받아 일어나는 것으로 해석되고 있다.
따라서, 원하는 표적 유전자만을 선택적으로 탈메틸화하고, 표적이 아닌 오프-타겟(off-target)에 대한 효과를 최소화할 수 있는 기술의 개발이 필요하다.
동물 세포에서 표적 DNA의 메틸화를 감소시키기 위한 조성물을 제공한다.
동물 세포에서 표적 DNA의 메틸화를 감소시키기 위한 키트를 제공한다.
동물 세포에서 표적 DNA를 탈메틸화시키는 방법을 제공한다.
일 양상은 DNA 탈메틸화 촉매 활성을 갖는 식물 유래 제1 폴리펩티드 및 표적 DNA에 특이적으로 결합하는 제2 폴리펩티드를 포함하는 융합 단백질, 또는 상기 융합 단백질을 암호화하는 폴리뉴클레오티드를 포함하는, 동물 세포에서 표적 DNA의 메틸화를 감소시키기 위한 조성물을 제공한다.
상기 식물 유래 제1 폴리펩티드는 애기장대(Arabidopsis thaliana) 유래 DNA 탈메틸화효소(demethylase)일 수 있다.
상기 제1 폴리펩티드는 DEMETER(DME) 또는 이의 변이체일 수 있다. 상기 DME는 서열번호 1의 아미노산 서열을 포함하는 폴리펩티드, 또는 이와 약 99% 이상, 약 95% 이상, 약 90% 이상, 약 80% 이상, 또는 약 70% 이상 서열 동일성을 갖는 폴리펩티드일 수 있다. 상기 DME는 Genbank accession No. AAM77215의 아미노산 서열을 포함할 수 있다.
상기 DEMETER 변이체는 서열번호 1의 아미노산 서열에서 N-말단으로부터 1 내지 677번째 아미노산 서열, 1 내지 687번째 아미노산 서열, 1 내지 697번째 아미노산 서열, 또는 1 내지 703번째 아미노산 서열이 결실(deletion)된 것일 수 있다. 상기 DEMETER 변이체는 서열번호 2 내지 5로 이루어진 군으로부터 선택된 아미노산 서열로 이루어진 것일 수 있다.
상기 제1 폴리펩티드는 DNA로부터 메틸화된 시토신을 절제(excise)하는 탈메틸화효소(demethylase)일 수 있다. 상기 제1 폴리펩티드는 뉴클레오티드의 글리코시드 결합(glycosidic bond)을 가수분해함으로써 DNA에서 메틸화된 시토신을 절제하는 DNA 글리코실라제(glycosylase)일 수 있다. 상기 메틸화된 시토신은 5-메틸시토신일 수 있다. 상기 제1 폴리펩티드는 5-메틸시토신 뉴클레오시드로부터 5-메틸시토신의 염기를 제거하는 염기 절제 수선(base excision repair)을 매개할 수 있다.
상기 제2 폴리펩티드는 유전체 편집 또는 유전체 교정(genome editing) 기술에 이용되는 것일 수 있다. 상기 제2 폴리펩티드는 DNA-결합 모티프를 포함할 수 있다. 예를 들어, 상기 제2 폴리펩티드는 TALE(Transcription Activator Like Effector) 폴리펩티드, Cas 폴리펩티드, 전사인자, 및 징크-핑거 뉴클레아제(Zinc-finger nuclease: ZFN)의 DNA-결합 도메인으로 이루어진 군으로부터 선택될 수 있다. 유전체 편집 기술은 유전체의 뉴클레오티드 서열을 변경시키는 반면에, DNA 탈메틸화 촉매 활성을 갖는 식물 유래 제1 폴리펩티드와 유전체 편집 기술을 결합시킴으로써 뉴클레오티드 서열의 변경 없이 특정 유전자의 발현 또는 활성을 조절할 수 있다.
상기 TALE(Transcription Activator Like Effector) 폴리펩티드는 TAL 이펙터 도메인으로도 불릴 수 있다. 상기 TALE 폴리펩티드는 하나 이상의 TALE-반복 모듈의 조합에 의해 서열-특이적 방식으로 표적 DNA에 특이적으로 결합할 수 있다. 상기 TALE 폴리펩티드는 TAL 이펙터 뉴클레아제로부터 뉴클레오티드 절단 도메인이 제거된 것일 수 있다.
상기 Cas 폴리펩티드는 CRISPR(Clustered Regularly Interspaced Short Palindromic Repeats) RNA(crRNA) 및 tracrRNA(trans-activating crRNA)와 복합체를 형성하여 이의 활성을 나타낼 수 있다. 상기 Cas 폴리펩티드는 활성 엔도뉴클레아제 또는 틈내기효소(nickase) 활성을 나타낼 수 있다. 상기 Cas 폴리펩티드는 스트렙토코커스 속(예, Streptococcus pyogenes), 네이세리아 속(예, Neisseria meningitidis), 파스테우렐라 속(예, Pasteurella multocida), 프란시셀라 속(예, Francisella novicida), 또는 캄필로박터 속(예, Campylobacter jejuni)의 세균으로부터 유래의 폴리펩티드일 수 있다. 상기 Cas 폴리펩티드는 재조합 단백질일 수 있다. 상기 Cas 폴리펩티드는 Cas9 폴리펩티드일 수 있다. 상기 Cas9 폴리펩티드는 야생형 Cas9(wild type Cas9: wtCas9), 틈내기효소 Cas9(nickase Cas9: nCas9), 및 촉매활성이 없는 Cas9(catalytically dead Cas9: dCas9)으로 이루어진 군으로부터 선택될 수 있다. 상기 wtCas9은 스트렙토코커스 피오게네스(Streptococcus pyogenes) 타입 II Cas9 엔도뉴클레아제(endonuclease)일 수 있다. 상기 nCas9은 wtCas9에서 두 활성 부위 중 하나인 N-말단으로부터 10번째 아미노산인 아스파르트산염(aspartate)이 알라닌으로 치환(D10A)되어, 가이드 RNA가 결합하는 DNA 서열만을 절단할 수 있는 변이체일 수 있다. 상기 dCas9은 wtCas9에서 RuvC 촉매 도메인의 두 활성 부위인 N-말단으로부터 10번째 아미노산인 아스파르트산염 및 840번째 아미노산인 히스티딘이 알라닌으로 치환(D10A 및 H840A)되어, 표적 DNA에 결합할 수 있으나 DNA 이중 가닥을 절단할 수 없는 변이체일 수 있다.
상기 전사인자(transcription factor)는 특정 DNA 서열에 결합함으로써 DNA로부터 메신저 RNA(messenger RNA: mRNA)로의 전사를 조절하는 단백질일 수 있다. 상기 전사인자는 하나 이상의 DNA-결합 도메인을 포함할 수 있다. 상기 DNA-결합 도메인은 예를 들어 염기성 헬릭스-루프-헬릭스, 염기성 류신 지퍼, 헬릭스-턴-헬릭스, 징크 핑거(Zinc-finger), 윙드(winged) 헬릭스, 윙드 헬릭스-턴-헬릭스, 헬릭스-루프-헬릭스 및 호메오도메인(homeodomain)이다.
상기 징크-핑거 뉴클레아제(Zinc-finger nuclease: ZFN)의 DNA-결합 도메인은 징크 핑거 단백질로도 불릴 수 있다. 상기 징크 핑거 단백질은 하나 이상의 징크 핑거 도메인을 포함할 수 있다.
상기 융합 단백질은 형광 단백질, 핵 위치 신호(nuclear localization signal: NLS), 링커 아미노산 서열, 또는 이들의 조합을 더 포함할 수 있다. 상기 형광 단백질은 상기 융합 단백질의 발현을 모니터링할 수 있는 바이오마커일 수 있다. 상기 형광 단백질은 예를 들어, 녹색 형광 단백질(green fluorescent protein: GFP), 황색 형광 단백질(yellow fluorescent protein: YFP), 적색 형광 단백질(red fluorescent protein: RFP), 및 시안 형광 단백질(cyan fluorescent protein: CFP)이다. 상기 NLS는 단백질이 세포핵으로 전달될 수 있는 신호 서열일 수 있다. 상기 NLS는 리신 또는 아르기닌을 다수 포함한 짧은 아미노산 서열일 수 있다. 상기 NLS는 예를 들어 서열번호 6의 아미노산 서열일 수 있다. 상기 링커 아미노산 서열은 단백질 도메인 사이를 이어주는 짧은 폴리펩티드 서열일 수 있다. 상기 링커 아미노산 서열은 서열번호 7, 서열번호 8, 또는 이들의 조합의 아미노산 서열을 포함할 수 있다.
상기 융합 단백질은 그의 N-말단으로부터 제2 폴리펩티드 및 제1 폴리펩티드의 순서로 연결된 것일 수 있다. 예를 들어, 상기 융합 단백질은 N-말단으로부터 TALE 및 DME의 순서; dCas9 및 DME의 순서; 또는 nCas9 및 DME의 순서로 연결된 것일 수 있다. 상기 융합 단백질은 N-말단으로부터 GFP, NLS, TALE, 링커 아미노산 서열, 및 DME의 순서; GFP, NLS, dCas9, NLS 및 DME의 순서; 또는 GFP, NLS, nCas9, NLS 및 DME의 순서로 연결된 것일 수 있다.
상기 폴리뉴클레오티드는 발현 벡터에 포함된 것일 수 있다. 상기 발현 벡터는 동물 세포에서 단백질을 발현시킬 수 있는 벡터일 수 있다.
상기 폴리뉴클레오티드는 표적 DNA에 상보적으로 결합할 수 있는 단일 가이드 RNA(single guide RNA: sgRNA), 프로모터, 폴리-아데노신(poly-adenosine: poly(A)) 서열, 또는 이들의 조합을 더 포함할 수 있다. 상기 sgRNA는 표적 DNA에 상보적인 짧은 길이의 단일가닥 RNA 서열로서, Cas 단백질과 복합체를 형성할 수 있고 Cas 단백질을 표적 DNA에 가져오는 RNA일 수 있다. 상기 sgRNA는 20 뉴클레오티드(nt) 염기쌍형성(base-pairing) 서열, 42 nt Cas9-결합 헤어핀 서열, 및 40 nt 터미네이터 서열을 포함할 수 있다. 상기 20 nt 염기쌍형성 서열은 표적 특이성을 부여하는 뉴클레오티드 서열로서, 표적 DNA에 따라 변형시킬 수 있다. 상기 프로모터는 유전자의 전사를 개시하는 DNA 영역을 말한다. 상기 프로모터는 CMV(cytomegalovirus) 프로모터, CMV 조기(immearly-early) 프로모터, SV(Simian Virus) 40 프로모터, 인간 유비퀴틴 C(Ubiquitin C: UBC) 프로모터, 인간 신장인자 1a(elongation factor 1a: EF1A) 프로모터, 마우스 포스포글리세레이트 키나제 1(phosphoglycerate kinase 1: PGK) 프로모터, CMV 조기(early)-인핸서에 연결된 닭 베타-액틴 프로모터(chicken b-Actin promoter coupled with CMV early enhancer: CAGG), 또는 이들의 조합일 수 있다. 폴리-아데노신 서열은 아데노신 모노포스페이트로 이루어진 길이가 긴 RNA 서열일 수 있다.
상기 동물 세포는 인간, 소, 말, 돼지, 개, 양, 염소, 고양이, 또는 마우스로부터 유래된 세포일 수 있다. 상기 동물 세포는 암세포, 심장 세포, 신경 세포, 베타 세포(beta cell: β-cell), 줄기세포, 또는 섬유세포(fibroblast cell)일 수 있다.
상기 조성물은 시험관 내(in vitro), 생체 내(in vivo), 또는 생체 외(ex vivo) 투여를 위한 조성물일 수 있다.
상기 표적 DNA는 조작하고자 하는 유전자 또는 이의 특정 뉴클레오티드일 수 있다. 상기 표적 DNA는 유전자의 인트론에 위치할 수 있다.
상기 메틸화의 감소는 유전체 중 표적 DNA에서 5-메틸시토신(5-methylcytosine: 5mC)의 빈도가 감소하는 것일 수 있다.
다른 양상은 DNA 탈메틸화 촉매 활성을 갖는 식물 유래 제1 폴리펩티드 및 표적 DNA에 특이적으로 결합하는 제2 폴리펩티드를 포함하는 융합 단백질, 또는 상기 융합 단백질을 암호화하는 폴리뉴클레오티드를 포함하는, 동물 세포에서 표적 DNA의 메틸화를 감소시키기 위한 키트를 제공한다.
상기 제1 폴리펩티드, 제2 폴리펩티드, 융합 단백질, 폴리뉴클레오티드, 동물 세포, 표적 DNA, 메틸화, 및 메틸화의 감소는 전술한 바와 같다.
상기 키트는 상기 동물 세포에 상기 융합 단백질 또는 폴리뉴클레오티드를 도입하기 위한 물질을 더 포함할 수 있다. 상기 키트는 형질전환, 형질도입, 형질감염, 또는 형질 주입에 필요한 시약을 포함할 수 있다. 예를 들어, 상기 키트는 리포펙타민(lipofectamine)을 포함할 수 있다.
다른 양상은 DNA 탈메틸화 촉매 활성을 갖는 식물 유래 제1 폴리펩티드 및 표적 DNA에 특이적으로 결합하는 제2 폴리펩티드를 포함하는 융합 단백질을 암호화하는 폴리뉴클레오티드와 동물 세포를 인큐베이션시켜 상기 폴리뉴클레오티드를 동물 세포에 도입하는 단계를 포함하는, 동물 세포에서 표적 DNA를 탈메틸화시키는 방법을 제공한다.
상기 제1 폴리펩티드, 제2 폴리펩티드, 융합 단백질, 폴리뉴클레오티드, 동물 세포, 표적 DNA, 메틸화, 및 메틸화의 감소는 전술한 바와 같다.
상기 방법은 상기 폴리뉴클레오티드와 동물 세포를 인큐베이션시켜 상기 폴리뉴클레오티드를 동물 세포에 도입하는 단계를 포함한다.
상기 도입은 형질전환, 형질도입, 형질감염, 또는 형질 주입일 수 있다.
상기 방법은 동물 세포에 도입된 상기 폴리뉴클레오티드가 상기 동물 세포에서 발현되고, 발현된 융합 단백질이 표적 DNA를 탈메틸화시킴으로써 표적 유전자의 발현을 유도할 수 있다.
일 양상에 따른 동물 세포에서 표적 DNA의 메틸화를 감소시키기 위한 조성물, 키트, 및 이를 이용한 동물 세포에서 표적 DNA를 탈메틸화시키는 방법에 따르면, DME에 의해 표적 DNA에 특이적으로 탈메틸화를 유도하여 표적 유전자의 발현을 특이적으로 유도할 수 있다. 또한, 기존의 5-아자시티딘이나 데시타빈 처리에 의한 비특이적 수동적 DNA 탈메틸화 기술을 대체할 수 있고, 임상적인 측면에서 표적 특이적 후성유전학적 치료 방법에 활용할 수 있다.
도 1은 유전체 편집 기술과 식물의 탈메틸화 효소인 DME를 이용한 표적 DNA의 탈메틸화 및 유전자 발현 유도 방법의 모식도이다.
도 2a는 TALE와 DME의 융합 단백질의 구성을 나타내는 모식도이고, 도 2b는 Oct4 프로모터 영역에서 표적 서열의 DNA 메틸화를 분석한 결과를 나타내는 그래프이다(x 축: 인트론 영역 중 위치(bp), y 축: CpG 메틸화 수준(%)).
도 3a는 sgRNA와 GFP-dCas9-DME가 하나의 벡터에 들어있는 모식도이고, 도 3b 및 도 3c는 각각 dCas9-DME 융합 단백질의 발현에 따른 표적 유전자인 RANKL 및 IFNβ의 상대적 발현 수준(변화 배수)를 나타내는 그래프이다.
도 4a는 sgRNA와 GFP-nCas9-DME가 하나의 벡터에 들어있는 모식도이고, 도 4b는 dCas9-DME 융합 단백질의 발현에 따른 표적 유전자인 RANKL 및 IFNβ의 상대적 발현 수준(변화 배수)를 나타내는 그래프이다.
도 2a는 TALE와 DME의 융합 단백질의 구성을 나타내는 모식도이고, 도 2b는 Oct4 프로모터 영역에서 표적 서열의 DNA 메틸화를 분석한 결과를 나타내는 그래프이다(x 축: 인트론 영역 중 위치(bp), y 축: CpG 메틸화 수준(%)).
도 3a는 sgRNA와 GFP-dCas9-DME가 하나의 벡터에 들어있는 모식도이고, 도 3b 및 도 3c는 각각 dCas9-DME 융합 단백질의 발현에 따른 표적 유전자인 RANKL 및 IFNβ의 상대적 발현 수준(변화 배수)를 나타내는 그래프이다.
도 4a는 sgRNA와 GFP-nCas9-DME가 하나의 벡터에 들어있는 모식도이고, 도 4b는 dCas9-DME 융합 단백질의 발현에 따른 표적 유전자인 RANKL 및 IFNβ의 상대적 발현 수준(변화 배수)를 나타내는 그래프이다.
이하 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.
실시예
1. 식물 DNA
탈메틸화
단백질을 이용한 동물 세포에서 표적 유전자의 활성화 유도
1. 식물 DNA
탈메틸화
효소와 TALE의 융합 단백질의 이용
식물의 DNA 탈메틸화 효소인 DEMETER(DME)와 전사 활성화물질-유사 작동인자(transcription activator-like effector: TAL effector 또는 TALE)의 융합 단백질이 동물 세포에서 표적 DNA를 탈메틸화시키는지 여부를 확인하였다.
Oct4의 프로모터를 표적으로 하는 TALE 모듈과 애기장대(Arabidopsis thaliana) 유래 DME의 융합 단백질을 암호화하는 벡터 pCDNA3.1-GFP-TALE-DMEΔN677+lnk를 준비하고, 그 모식도를 도 2a에 나타내었다.
상기 벡터에서, Mok, Y. G. et al., Proc. Natl. Acad. Sci. USA, 2010, vol.107, pp.19225-19230에 기재된 바와 같이, DME는 5-메틸시토신 제거 활성을 갖는 애기장대 유래 DME(서열번호 1; Genbank accession No. AAM77215.1; Choi et al., Cell, vol.110, pp.33-42, July 12, 2002)로부터 활성에 불필요한 부분을 제거하고 도메인 A, 글리코실라제(glycosylase) 도메인 및 도메인 B를 포함하도록 변형되었다. 또한, DME는 N-말단으로부터 1 내지 677번째 뉴클레오티드에 DNA 결합 활성을 갖는 부위가 있고, 이 부위가 존재할 경우 표적이 아닌 핵산이 탈메틸화 되는 오프-타겟(off-target)이 생길 가능성이 있다. 따라서, N-말단을 부분적으로 제거하면서 오프-타겟이 존재하지 않는 DME 변이체인 DMEΔN677(서열번호 2), DMEΔN687(서열번호 3), DMEΔN697(서열번호 4), 및 DMEΔN703(서열번호 5)을 준비하였다. 도 1b에서, "GFP"는 녹색 형광 단백질(green fluorescence protein)을 나타내고, "NLS"는 핵 위치 신호(nuclear localization signal)(서열번호 6)를 나타내고, "TALE"는 Oct4 프로모터를 표적으로 하는 TALE 모듈(Toolgen, Inc.)을 나타내고, "GGGS"는 N-Gly-Gly-Gly-Ser-C의 링커 서열(서열번호 7)을 나타내고, "링커" 또는 "lnk"는 N-AGSSGNGSSGNG-C의 링커 서열(서열번호 8)을 나타내고, "IDR2"는 도메인간 부위 2(interdomain region 2)을 나타낸다. 또한, 음성 대조군으로 GFP가 클로닝된 pCDNA3.1를 준비하였다.
5x105 개의 동물세포 HEK(Human embryonic kidney)-293T를 60 mm 세포배양 접시에 접종하고, 37℃ 및 5% CO2에서 약 24 시간 동안 배양하였다. 준비된 벡터들은 리포펙타민 2000(Thermo Fisher Scientific)을 사용하여 HEK-293T에 형질전환시켰다. 약 48시간 후, FACS Aria III(BD Bioscience)를 사용하여 녹색 형광 단백질이 발현되는 세포만을 분리하여 형질전환된 세포를 수득하였다. 수득된 세포를 원심 분리하여 모은 후 세포로부터 게놈 DNA를 분리하였다. 분리된 게놈 DNA를 EZ DNA 메틸화-골드 키트(Zymo research)을 사용하여 중아황산염(bisulfite)를 처리하였다. 중아황산염을 처리한 DNA와 하기 프라이머 쌍을 사용하여 중합효소 연쇄 반응(PCR)을 수행하여, Oct4 프로모터의 표적 서열을 증폭하였다. PCR에서 어닐링 온도는 58℃였다.
정방향 프라이머: 5'-GTTTTGGGGTTATTAAGAGTTATTGAAYGAGGG-3' (서열번호 9)
역방향 프라이머: 5'-CCCAAAACRCCAACRCTACAATC-3' (서열번호 10)
PCR 산물을 T-벡터에 클로닝하고 시퀀싱하였다. Oct4 프로모터 영역에서 표적 서열의 DNA 메틸화를 분석한 결과를 도 2b에 나타내었다.
도 2b에 나타난 바와 같이, 유전체 편집 기술 중 하나인 TALE 모듈과 N-말단이 제거된 DMEΔN697+lnk의 융합 단백질이 표적 DNA를 탈메틸화시킨다는 것을 확인하였다.
2. 식물 DNA
탈메틸화
효소와
Cas9
의 융합 단백질의 이용
(1)
CRISPR
/
dCas9
-
DME
에 의한 표적 유전자의 발현 유도
CRISPR/Cas9 시스템은 단일 가이드 RNA(single guide RNA: sgRNA)가 표적 DNA를 인지하는 방법으로서, 단백질이 표적 DNA를 인지하는 TALE 모듈에 비해 표적 DNA 염기서열에 정확히 결합할 수 있다. 또한 표적 DNA 염기서열을 결정하기 쉽고, sgRNA를 합성하기 쉬운 장점이 있다. CRISPR/dCas9은 Cas9에 있는 두 개의 절단 활성 부위를 돌연변이시켜(D10A/H840A), 표적 DNA를 인식할 수 있지만 절단할 수 없는 돌연변이체다. 실시예 1.1과 같이, DME와 CRISPR/dCas9의 융합 단백질이 표적 DNA를 탈메틸화시켜 발현을 유도할 수 있는지 여부를 확인하였다.
sgRNA와 GFP-dCas9-DME가 하나의 벡터에 들어 있는 시스템을 이용하였다. 구체적으로, nCas9(D10A 절단효소 돌연변이체)를 포함하는 pX460 벡터(Addgene, plasmid #48873)를 준비하였다. pX460 벡터의 AgeI 및 EcoRI 부위에 다중 클로닝 부위(multiple cloning site: MCS)를 삽입하여 pCbh를 제조하였다. GFP를 암호화하는 핵산 단편을 증폭하고, pCbh의 NheI 및 MluI 부위에 클로닝하여 pCbh-GFP를 제조하였다. 하기 프라이머를 사용하여 부위-특이적 돌연변이시켜 촉매 활성이 제거된 Cas9(catalytically dead Cas9: dCas9)을 준비하였다. dCas9은 pX460(Addgene, plasmid #48873)에 있는 nCas9(D10A)으로부터 하기 서열을 이용하여 H840A 돌연변이를 준비하였다.
정방향: 5'-ccgactacgatgtggacgccatcgtgcctcagagctttctg-3' (서열번호 11)
역방향: 5'-cagaaagctctgaggcacgatggcgtccacatcgtagtcgg-3' (서열번호 12)
dCas9 단편을 하기 서열을 이용하여 증폭하고, 증폭된 dCas9 단편을 pCbh-GFP의 MluI 및 SpeI 부위에 클로닝하여 pCbh-GFP-dCas9를 제조하였다.
정방향: 5'-aattacgcgtatggactataaggaccacgacgg-3' (서열번호 13)
역방향: 5'-aattactagtctttttcttttttgcctggccggc-3' (서열번호 14)
실시예 1.1에 기재된 바와 같이 준비된 DMEΔN677+lnk 및 DMEΔN697+lnk을 준비하였다. 음성 대조군으로 DME를 도입하지 않은 dCas9만 삽입된 벡터를 사용하였고, 비교군으로 DME 대신에 TET1 촉매 도메인(catalytic domain: CD)가 삽입된 벡터를 사용하였다. DME와 TET1CD 서열에서 BbsI 부위를 제거하기 위해 하기 서열을 이용하여 부위-특이적 돌연변이시켰다.
DME BbsI 부위 돌연변이 서열
정방향: 5'-ggaagaagaaagaagagtctttcgaggaagggctgattcc-3' (서열번호 15)
역방향: 5'-ggaatcagcccttcctcgaaagactcttctttcttcttcc-3' (서열번호 16)
정방향: 5'-gtccgtggattcgaacagaaaacaagagcaccgcgtcc-3' (서열번호 17)
역방향: 5'-ggacgcggtgctcttgttttctgttcgaatccacggac-3' (서열번호 18)
Tet1CD BbsI 부위 돌연변이 서열
정방향: 5'-ggcttctcctggtccccgaaAactgcttcagccacaccag-3' (서열번호 19)
역방향: 5'-ctggtgtggctgaagcagtTttcggggaccaggagaagcc-3' (서열번호 20)
정방향: 5'-ctgtacgatgccttcgggaaAactcagtggtgccaatgcag-3' (서열번호 21)
역방향: 5'-ctgcattggcaccactgagtTttcccgaaggcatcgtacag-3' (서열번호 22)
pCbh-GFP-dCas9
DMEΔN677+lnk 증폭용 프라이머
정방향: 5'-aattactagttacaaaggagatggtgcacttg-3' (서열번호 23)
역방향: 5'-aattgtttaaacttaggttttgttgttcttcaatttg-3' (서열번호 24)
DMEΔN697+lnk 증폭용 프라이머
정방향: 5'-aattactagtgttgacattgacgatgaaac-3' (서열번호 25)
역방향: 5'-aattgtttaaacttaggttttgttgttcttcaatttg-3' (서열번호 26)
TET1CD 증폭용 프라이머
정방향: 5'-aattactagtgaactgcccacctgcagctgtc-3' (서열번호 27)
역방향: 5'-aattgtttaaactcagacccaatggttatagggcc-3' (서열번호 28)
돌연변이된 DME와 TET1CD 단편을 SpeI 및 PmeI으로 절단하고 pCbh-GFP-dCas9으로 삽입하였다.
RANKL을 표적으로 하는 sgRNA를 하기 상보성 프라이머 쌍으로 어닐링하여 pCbh-GFP-dCas9의 BsbI 부위로 삽입하여, pCbh-sgRNA(RANKL)-GFP-dCas9-DME를 제조하였다.
정방향: 5'-caccgcaaggggagtctggaaccac-3' (서열번호 29)
역방향: 5'-aaacgtggttccagactccccttgc-3' (서열번호 30)
RANKL 표적 서열: 5'-caaggggagtctggaaccac-3'(서열번호 31)이다.
제조된 pCbh-sgRNA(RANKL)-GFP-dCas9-DME의 모식도를 도 3a에 나타내었다.
실시예 1.1에 기재된 바와 같이, pCbh-sgRNA(RANKL)-GFP-dCas9-DME를 HEK-293T 세포에 칼슘 인산염 공침전(coprecipitation) 방법을 이용하여 형질감염시켰다. 형질감염 후 약 24 시간에 DMEM 배지를 교환하였다. 형질감염 후 약 48 시간에 세포를 수득하고, FACS Aria III(BD Bioscience)를 사용하여 GFP 발현 세포를 분리하였다.
표적인 RANKL과 오프-타겟인 인터페론 베타(interferon beta: IFNβ)의 발현 수준을 측정하기 위해 정량적 RT-PCR를 수행하였다. RNeasy mini kit(QIAGEN)를 사용하여 분리된 세포로부터 총 RNA를 수득하였다. 1 ㎍의 총 RNA를 역전사효소를 사용하여 상보적 DNA(cDNA)를 합성하였다. 60 ng의 cDNA는 하기 프라이머 쌍을 이용하여 정량적 RT-PCR을 수행하였다.
RANKL 정방향 프라이머: 5'-actattaatgccaccgaca-3' (서열번호 32)
RANKL 역방향 프라이머: 5'-agggtatgagaacttgggat-3' (서열번호 33)
IFNβ 정방향 프라이머: 5'-cattacctgaaggccaagga-3' (서열번호 34)
IFNβ 역방향 프라이머: 5'-cagcatctgctggttgaaga-3' (서열번호 35)
GAPDH 정방향 프라이머: 5'-gagtcaacggatttggtcgt-3' (서열번호 36)
GAPDH 역방향 프라이머: 5'-gacaagcttcccgttctcag-3' (서열번호 37)
정량적 RT-PCR 결과는 dCas9 음성 대조군에 대해 정규화하여 상대적 발현 수준을 분석하였다. RANKL 및 IFNβ의 상대적 발현 수준을 각각 도 3b 및 도 3c에 나타내었다.
도 3b 및 도 3c에 나타난 바와 같이, 표적 유전자인 RANKL의 발현은 GFP-dCas9-DMEΔN697+lnk에 의해 증가하였다. 또한, GFP-dCas9-DMEΔN677+lnk는 IFNβ의 발현이 증가한 반면에, GFP-dCas9-DMEΔN697+lnk는 IFNβ의 발현이 유의하게 증가하지 않았다. 따라서, GFP-dCas9-DME 융합 단백질은 오프-타겟 없이 표적 유전자의 발현을 증가시키는 것을 확인하였다.
(2)
CRISPR
/
nCas9
-
DME
에 의한 표적 유전자의 발현 유도
nCas9은 Cas9에 있는 두 개의 절단 활성 부위 중 하나만 돌연변이시켜(D10A), sgRNA가 결합하는 DNA 서열만을 절단할 수 있는 돌연변이체다. DME와 CRISPR/nCas9의 융합 단백질이 표적 DNA를 탈메틸화시켜 발현을 유도할 수 있는지 여부를 확인하였다.
nCas9(D10A 절단효소 돌연변이체)를 포함하는 pX460 벡터(Addgene, plasmid #48873)를 이용하고 실시예 1.2(1)에 기재된 방법과 유사하게 pCbh-sgRNA(RANKL)-GFP-nCas9-DME를 제조하였다. pCbh-sgRNA(RANKL)-GFP-nCas9-DME의 모식도를 도 4a에 나타내었다.
실시예 1.1에 기재된 바와 같이, pCbh-sgRNA(RANKL)-GFP-nCas9-DME를 HEK-293T 세포에 칼슘 인산염 공침전 방법을 이용하여 형질감염시켰다. 형질감염 후 약 24 시간에 DMEM 배지를 교환하였다. 형질감염 후 약 48 시간에 세포를 수득하고, FACS Aria III(BD Bioscience)를 사용하여 GFP 발현 세포를 분리하였다. 표적인 RANKL과 오프-타겟인 IFNβ의 발현 수준을 측정하기 위해 정량적 RT-PCR를 수행하였다. 정량적 RT-PCR 결과는 nCas9 음성 대조군에 대해 정규화하여 상대적 발현 수준을 분석하였다. RANKL 및 IFNβ의 상대적 발현 수준을 도 4b에 나타내었다.
도 4b에 나타난 바와 같이, 표적 유전자인 RANKL의 발현은 GFP-nCas9-DMEΔN697+lnk에 의해 약 5.5배 증가하였다. GFP-nCas9-DMEΔN677+lnk는 IFNβ의 발현이 약 5배 증가한 반면에, GFP-nCas9-DMEΔN697+lnk는 IFNβ의 발현이 유의하게 증가하지 않았다. 또한, DMEΔN697+lnk은 동물의 DNA 탈메틸화에 관여하는 Tet1에 비해 표적 유전자의 발현이 약 2.5배 더 증가하였다. 따라서, GFP-nCas9-DME 융합 단백질은 오프-타겟 없이 표적 유전자의 발현을 강력하게 유도하는 것을 확인하였다.
아울러, 도 3b와 도 4b에 나타난 바와 같이, DME를 유전체 편집 기술 중 하나인 CRISPR/Cas9 시스템과 결합하여 표적 유전자의 발현이 증가하는 것을 확인하였다. 하지만, 두 개의 활성 부위 모두 돌연변이된 CRSPR/dCas9에 비해 두 개의 활성 부위 중 하나만 돌연변이된 CRISPR/nCas9에 DME를 결합하였을 때 표적 유전자의 발현이 더 증가하였다.
<110> SEOUL NATIONAL UNIVERSITY R&DB Foundation
<120> Composition and kit for reducing methylation of target DNA and
induction of expression of target gene in animal cell, and method
using the same
<130> GN-121261-KR
<160> 37
<170> KoPatentIn 3.0
<210> 1
<211> 1729
<212> PRT
<213> Artificial Sequence
<220>
<223> DEMETER protein [Arabidopsis thaliana]
<400> 1
Met Gln Ser Ile Met Asp Ser Ser Ala Val Asn Ala Thr Glu Ala Thr
1 5 10 15
Glu Gln Asn Asp Gly Ser Arg Gln Asp Val Leu Glu Phe Asp Leu Asn
20 25 30
Lys Thr Pro Gln Gln Lys Pro Ser Lys Arg Lys Arg Lys Phe Met Pro
35 40 45
Lys Val Val Val Glu Gly Lys Pro Lys Arg Lys Pro Arg Lys Pro Ala
50 55 60
Glu Leu Pro Lys Val Val Val Glu Gly Lys Pro Lys Arg Lys Pro Arg
65 70 75 80
Lys Ala Ala Thr Gln Glu Lys Val Lys Ser Lys Glu Thr Gly Ser Ala
85 90 95
Lys Lys Lys Asn Leu Lys Glu Ser Ala Thr Lys Lys Pro Ala Asn Val
100 105 110
Gly Asp Met Ser Asn Lys Ser Pro Glu Val Thr Leu Lys Ser Cys Arg
115 120 125
Lys Ala Leu Asn Phe Asp Leu Glu Asn Pro Gly Asp Ala Arg Gln Gly
130 135 140
Asp Ser Glu Ser Glu Ile Val Gln Asn Ser Ser Gly Ala Asn Ser Phe
145 150 155 160
Ser Glu Ile Arg Asp Ala Ile Gly Gly Thr Asn Gly Ser Phe Leu Asp
165 170 175
Ser Val Ser Gln Ile Asp Lys Thr Asn Gly Leu Gly Ala Met Asn Gln
180 185 190
Pro Leu Glu Val Ser Met Gly Asn Gln Pro Asp Lys Leu Ser Thr Gly
195 200 205
Ala Lys Leu Ala Arg Asp Gln Gln Pro Asp Leu Leu Thr Arg Asn Gln
210 215 220
Gln Cys Gln Phe Pro Val Ala Thr Gln Asn Thr Gln Phe Pro Met Glu
225 230 235 240
Asn Gln Gln Ala Trp Leu Gln Met Lys Asn Gln Leu Ile Gly Phe Pro
245 250 255
Phe Gly Asn Gln Gln Pro Arg Met Thr Ile Arg Asn Gln Gln Pro Cys
260 265 270
Leu Ala Met Gly Asn Gln Gln Pro Met Tyr Leu Ile Gly Thr Pro Arg
275 280 285
Pro Ala Leu Val Ser Gly Asn Gln Gln Leu Gly Gly Pro Gln Gly Asn
290 295 300
Lys Arg Pro Ile Phe Leu Asn His Gln Thr Cys Leu Pro Ala Gly Asn
305 310 315 320
Gln Leu Tyr Gly Ser Pro Thr Asp Met His Gln Leu Val Met Ser Thr
325 330 335
Gly Gly Gln Gln His Gly Leu Leu Ile Lys Asn Gln Gln Pro Gly Ser
340 345 350
Leu Ile Arg Gly Gln Gln Pro Cys Val Pro Leu Ile Asp Gln Gln Pro
355 360 365
Ala Thr Pro Lys Gly Phe Thr His Leu Asn Gln Met Val Ala Thr Ser
370 375 380
Met Ser Ser Pro Gly Leu Arg Pro His Ser Gln Ser Gln Val Pro Thr
385 390 395 400
Thr Tyr Leu His Val Glu Ser Val Ser Arg Ile Leu Asn Gly Thr Thr
405 410 415
Gly Thr Cys Gln Arg Ser Arg Ala Pro Ala Tyr Asp Ser Leu Gln Gln
420 425 430
Asp Ile His Gln Gly Asn Lys Tyr Ile Leu Ser His Glu Ile Ser Asn
435 440 445
Gly Asn Gly Cys Lys Lys Ala Leu Pro Gln Asn Ser Ser Leu Pro Thr
450 455 460
Pro Ile Met Ala Lys Leu Glu Glu Ala Arg Gly Ser Lys Arg Gln Tyr
465 470 475 480
His Arg Ala Met Gly Gln Thr Glu Lys His Asp Leu Asn Leu Ala Gln
485 490 495
Gln Ile Ala Gln Ser Gln Asp Val Glu Arg His Asn Ser Ser Thr Cys
500 505 510
Val Glu Tyr Leu Asp Ala Ala Lys Lys Thr Lys Ile Gln Lys Val Val
515 520 525
Gln Glu Asn Leu His Gly Met Pro Pro Glu Val Ile Glu Ile Glu Asp
530 535 540
Asp Pro Thr Asp Gly Ala Arg Lys Gly Lys Asn Thr Ala Ser Ile Ser
545 550 555 560
Lys Gly Ala Ser Lys Gly Asn Ser Ser Pro Val Lys Lys Thr Ala Glu
565 570 575
Lys Glu Lys Cys Ile Val Pro Lys Thr Pro Ala Lys Lys Gly Arg Ala
580 585 590
Gly Arg Lys Lys Ser Val Pro Pro Pro Ala His Ala Ser Glu Ile Gln
595 600 605
Leu Trp Gln Pro Thr Pro Pro Lys Thr Pro Leu Ser Arg Ser Lys Pro
610 615 620
Lys Gly Lys Gly Arg Lys Ser Ile Gln Asp Ser Gly Lys Ala Arg Gly
625 630 635 640
Pro Ser Gly Glu Leu Leu Cys Gln Asp Ser Ile Ala Glu Ile Ile Tyr
645 650 655
Arg Met Gln Asn Leu Tyr Leu Gly Asp Lys Glu Arg Glu Gln Glu Gln
660 665 670
Asn Ala Met Val Leu Tyr Lys Gly Asp Gly Ala Leu Val Pro Tyr Glu
675 680 685
Ser Lys Lys Arg Lys Pro Arg Pro Lys Val Asp Ile Asp Asp Glu Thr
690 695 700
Thr Arg Ile Trp Asn Leu Leu Met Gly Lys Gly Asp Glu Lys Glu Gly
705 710 715 720
Asp Glu Glu Lys Asp Lys Lys Lys Glu Lys Trp Trp Glu Glu Glu Arg
725 730 735
Arg Val Phe Arg Gly Arg Ala Asp Ser Phe Ile Ala Arg Met His Leu
740 745 750
Val Gln Gly Asp Arg Arg Phe Ser Pro Trp Lys Gly Ser Val Val Asp
755 760 765
Ser Val Ile Gly Val Phe Leu Thr Gln Asn Val Ser Asp His Leu Ser
770 775 780
Ser Ser Ala Phe Met Ser Leu Ala Ala Arg Phe Pro Pro Lys Leu Ser
785 790 795 800
Ser Ser Arg Glu Asp Glu Arg Asn Val Arg Ser Val Val Val Glu Asp
805 810 815
Pro Glu Gly Cys Ile Leu Asn Leu Asn Glu Ile Pro Ser Trp Gln Glu
820 825 830
Lys Val Gln His Pro Ser Asp Met Glu Val Ser Gly Val Asp Ser Gly
835 840 845
Ser Lys Glu Gln Leu Arg Asp Cys Ser Asn Ser Gly Ile Glu Arg Phe
850 855 860
Asn Phe Leu Glu Lys Ser Ile Gln Asn Leu Glu Glu Glu Val Leu Ser
865 870 875 880
Ser Gln Asp Ser Phe Asp Pro Ala Ile Phe Gln Ser Cys Gly Arg Val
885 890 895
Gly Ser Cys Ser Cys Ser Lys Ser Asp Ala Glu Phe Pro Thr Thr Arg
900 905 910
Cys Glu Thr Lys Thr Val Ser Gly Thr Ser Gln Ser Val Gln Thr Gly
915 920 925
Ser Pro Asn Leu Ser Asp Glu Ile Cys Leu Gln Gly Asn Glu Arg Pro
930 935 940
His Leu Tyr Glu Gly Ser Gly Asp Val Gln Lys Gln Glu Thr Thr Asn
945 950 955 960
Val Ala Gln Lys Lys Pro Asp Leu Glu Lys Thr Met Asn Trp Lys Asp
965 970 975
Ser Val Cys Phe Gly Gln Pro Arg Asn Asp Thr Asn Trp Gln Thr Thr
980 985 990
Pro Ser Ser Ser Tyr Glu Gln Cys Ala Thr Arg Gln Pro His Val Leu
995 1000 1005
Asp Ile Glu Asp Phe Gly Met Gln Gly Glu Gly Leu Gly Tyr Ser Trp
1010 1015 1020
Met Ser Ile Ser Pro Arg Val Asp Arg Val Lys Asn Lys Asn Val Pro
1025 1030 1035 1040
Arg Arg Phe Phe Arg Gln Gly Gly Ser Val Pro Arg Glu Phe Thr Gly
1045 1050 1055
Gln Ile Ile Pro Ser Thr Pro His Glu Leu Pro Gly Met Gly Leu Ser
1060 1065 1070
Gly Ser Ser Ser Ala Val Gln Glu His Gln Asp Asp Thr Gln His Asn
1075 1080 1085
Gln Gln Asp Glu Met Asn Lys Ala Ser His Leu Gln Lys Thr Phe Leu
1090 1095 1100
Asp Leu Leu Asn Ser Ser Glu Glu Cys Leu Thr Arg Gln Ser Ser Thr
1105 1110 1115 1120
Lys Gln Asn Ile Thr Asp Gly Cys Leu Pro Arg Asp Arg Thr Ala Glu
1125 1130 1135
Asp Val Val Asp Pro Leu Ser Asn Asn Ser Ser Leu Gln Asn Ile Leu
1140 1145 1150
Val Glu Ser Asn Ser Ser Asn Lys Glu Gln Thr Ala Val Glu Tyr Lys
1155 1160 1165
Glu Thr Asn Ala Thr Ile Leu Arg Glu Met Lys Gly Thr Leu Ala Asp
1170 1175 1180
Gly Lys Lys Pro Thr Ser Gln Trp Asp Ser Leu Arg Lys Asp Val Glu
1185 1190 1195 1200
Gly Asn Glu Gly Arg Gln Glu Arg Asn Lys Asn Asn Met Asp Ser Ile
1205 1210 1215
Asp Tyr Glu Ala Ile Arg Arg Ala Ser Ile Ser Glu Ile Ser Glu Ala
1220 1225 1230
Ile Lys Glu Arg Gly Met Asn Asn Met Leu Ala Val Arg Ile Lys Asp
1235 1240 1245
Phe Leu Glu Arg Ile Val Lys Asp His Gly Gly Ile Asp Leu Glu Trp
1250 1255 1260
Leu Arg Glu Ser Pro Pro Asp Lys Ala Lys Asp Tyr Leu Leu Ser Ile
1265 1270 1275 1280
Arg Gly Leu Gly Leu Lys Ser Val Glu Cys Val Arg Leu Leu Thr Leu
1285 1290 1295
His Asn Leu Ala Phe Pro Val Asp Thr Asn Val Gly Arg Ile Ala Val
1300 1305 1310
Arg Met Gly Trp Val Pro Leu Gln Pro Leu Pro Glu Ser Leu Gln Leu
1315 1320 1325
His Leu Leu Glu Leu Tyr Pro Val Leu Glu Ser Ile Gln Lys Phe Leu
1330 1335 1340
Trp Pro Arg Leu Cys Lys Leu Asp Gln Arg Thr Leu Tyr Glu Leu His
1345 1350 1355 1360
Tyr Gln Leu Ile Thr Phe Gly Lys Val Phe Cys Thr Lys Ser Arg Pro
1365 1370 1375
Asn Cys Asn Ala Cys Pro Met Arg Gly Glu Cys Arg His Phe Ala Ser
1380 1385 1390
Ala Tyr Ala Ser Ala Arg Leu Ala Leu Pro Ala Pro Glu Glu Arg Ser
1395 1400 1405
Leu Thr Ser Ala Thr Ile Pro Val Pro Pro Glu Ser Phe Pro Pro Val
1410 1415 1420
Ala Ile Pro Met Ile Glu Leu Pro Leu Pro Leu Glu Lys Ser Leu Ala
1425 1430 1435 1440
Ser Gly Ala Pro Ser Asn Arg Glu Asn Cys Glu Pro Ile Ile Glu Glu
1445 1450 1455
Pro Ala Ser Pro Gly Gln Glu Cys Thr Glu Ile Thr Glu Ser Asp Ile
1460 1465 1470
Glu Asp Ala Tyr Tyr Asn Glu Asp Pro Asp Glu Ile Pro Thr Ile Lys
1475 1480 1485
Leu Asn Ile Glu Gln Phe Gly Met Thr Leu Arg Glu His Met Glu Arg
1490 1495 1500
Asn Met Glu Leu Gln Glu Gly Asp Met Ser Lys Ala Leu Val Ala Leu
1505 1510 1515 1520
His Pro Thr Thr Thr Ser Ile Pro Thr Pro Lys Leu Lys Asn Ile Ser
1525 1530 1535
Arg Leu Arg Thr Glu His Gln Val Tyr Glu Leu Pro Asp Ser His Arg
1540 1545 1550
Leu Leu Asp Gly Met Asp Lys Arg Glu Pro Asp Asp Pro Ser Pro Tyr
1555 1560 1565
Leu Leu Ala Ile Trp Thr Pro Gly Glu Thr Ala Asn Ser Ala Gln Pro
1570 1575 1580
Pro Glu Gln Lys Cys Gly Gly Lys Ala Ser Gly Lys Met Cys Phe Asp
1585 1590 1595 1600
Glu Thr Cys Ser Glu Cys Asn Ser Leu Arg Glu Ala Asn Ser Gln Thr
1605 1610 1615
Val Arg Gly Thr Leu Leu Ile Pro Cys Arg Thr Ala Met Arg Gly Ser
1620 1625 1630
Phe Pro Leu Asn Gly Thr Tyr Phe Gln Val Asn Glu Leu Phe Ala Asp
1635 1640 1645
His Glu Ser Ser Leu Lys Pro Ile Asp Val Pro Arg Asp Trp Ile Trp
1650 1655 1660
Asp Leu Pro Arg Arg Thr Val Tyr Phe Gly Thr Ser Val Thr Ser Ile
1665 1670 1675 1680
Phe Arg Gly Leu Ser Thr Glu Gln Ile Gln Phe Cys Phe Trp Lys Gly
1685 1690 1695
Phe Val Cys Val Arg Gly Phe Glu Gln Lys Thr Arg Ala Pro Arg Pro
1700 1705 1710
Leu Met Ala Arg Leu His Phe Pro Ala Ser Lys Leu Lys Asn Asn Lys
1715 1720 1725
Thr
<210> 2
<211> 673
<212> PRT
<213> Artificial Sequence
<220>
<223> DME deltaN677+lnk
<400> 2
Tyr Lys Gly Asp Gly Ala Leu Val Pro Tyr Glu Ser Lys Lys Arg Lys
1 5 10 15
Pro Arg Pro Lys Val Asp Ile Asp Asp Glu Thr Thr Arg Ile Trp Asn
20 25 30
Leu Leu Met Gly Lys Gly Asp Glu Lys Glu Gly Asp Glu Glu Lys Asp
35 40 45
Lys Lys Lys Glu Lys Trp Trp Glu Glu Glu Arg Arg Val Phe Arg Gly
50 55 60
Arg Ala Asp Ser Phe Ile Ala Arg Met His Leu Val Gln Gly Asp Arg
65 70 75 80
Arg Phe Ser Pro Trp Lys Gly Ser Val Val Asp Ser Val Ile Gly Val
85 90 95
Phe Leu Thr Gln Asn Val Ser Asp His Leu Ser Ser Ser Ala Phe Met
100 105 110
Ser Leu Ala Ala Arg Phe Pro Pro Ala Gly Ser Ser Gly Asn Gly Ser
115 120 125
Ser Gly Asn Gly Thr Ser Gln Trp Asp Ser Leu Arg Lys Asp Val Glu
130 135 140
Gly Asn Glu Gly Arg Gln Glu Arg Asn Lys Asn Asn Met Asp Ser Ile
145 150 155 160
Asp Tyr Glu Ala Ile Arg Arg Ala Ser Ile Ser Glu Ile Ser Glu Ala
165 170 175
Ile Lys Glu Arg Gly Met Asn Asn Met Leu Ala Val Arg Ile Lys Asp
180 185 190
Phe Leu Glu Arg Ile Val Lys Asp His Gly Gly Ile Asp Leu Glu Trp
195 200 205
Leu Arg Glu Ser Pro Pro Asp Lys Ala Lys Asp Tyr Leu Leu Ser Ile
210 215 220
Arg Gly Leu Gly Leu Lys Ser Val Glu Cys Val Arg Leu Leu Thr Leu
225 230 235 240
His Asn Leu Ala Phe Pro Val Asp Thr Asn Val Gly Arg Ile Ala Val
245 250 255
Arg Met Gly Trp Val Pro Leu Gln Pro Leu Pro Glu Ser Leu Gln Leu
260 265 270
His Leu Leu Glu Leu Tyr Pro Val Leu Glu Ser Ile Gln Lys Phe Leu
275 280 285
Trp Pro Arg Leu Cys Lys Leu Asp Gln Arg Thr Leu Tyr Glu Leu His
290 295 300
Tyr Gln Leu Ile Thr Phe Gly Lys Val Phe Cys Thr Lys Ser Arg Pro
305 310 315 320
Asn Cys Asn Ala Cys Pro Met Arg Gly Glu Cys Arg His Phe Ala Ser
325 330 335
Ala Tyr Ala Ser Ala Arg Leu Ala Leu Pro Ala Pro Glu Glu Arg Ser
340 345 350
Leu Thr Ser Ala Thr Ile Pro Val Pro Pro Glu Ser Phe Pro Pro Val
355 360 365
Ala Ile Pro Met Ile Glu Leu Pro Leu Pro Leu Glu Lys Ser Leu Ala
370 375 380
Ser Gly Ala Pro Ser Asn Arg Glu Asn Cys Glu Pro Ile Ile Glu Glu
385 390 395 400
Pro Ala Ser Pro Gly Gln Glu Cys Thr Glu Ile Thr Glu Ser Asp Ile
405 410 415
Glu Asp Ala Tyr Tyr Asn Glu Asp Pro Asp Glu Ile Pro Thr Ile Lys
420 425 430
Leu Asn Ile Glu Gln Phe Gly Met Thr Leu Arg Glu His Met Glu Arg
435 440 445
Asn Met Glu Leu Gln Glu Gly Asp Met Ser Lys Ala Leu Val Ala Leu
450 455 460
His Pro Thr Thr Thr Ser Ile Pro Thr Pro Lys Leu Lys Asn Ile Ser
465 470 475 480
Arg Leu Arg Thr Glu His Gln Val Tyr Glu Leu Pro Asp Ser His Arg
485 490 495
Leu Leu Asp Gly Met Asp Lys Arg Glu Pro Asp Asp Pro Ser Pro Tyr
500 505 510
Leu Leu Ala Ile Trp Thr Pro Gly Glu Thr Ala Asn Ser Ala Gln Pro
515 520 525
Pro Glu Gln Lys Cys Gly Gly Lys Ala Ser Gly Lys Met Cys Phe Asp
530 535 540
Glu Thr Cys Ser Glu Cys Asn Ser Leu Arg Glu Ala Asn Ser Gln Thr
545 550 555 560
Val Arg Gly Thr Leu Leu Ile Pro Cys Arg Thr Ala Met Arg Gly Ser
565 570 575
Phe Pro Leu Asn Gly Thr Tyr Phe Gln Val Asn Glu Leu Phe Ala Asp
580 585 590
His Glu Ser Ser Leu Lys Pro Ile Asp Val Pro Arg Asp Trp Ile Trp
595 600 605
Asp Leu Pro Arg Arg Thr Val Tyr Phe Gly Thr Ser Val Thr Ser Ile
610 615 620
Phe Arg Gly Leu Ser Thr Glu Gln Ile Gln Phe Cys Phe Trp Lys Gly
625 630 635 640
Phe Val Cys Val Arg Gly Phe Glu Gln Lys Thr Arg Ala Pro Arg Pro
645 650 655
Leu Met Ala Arg Leu His Phe Pro Ala Ser Lys Leu Lys Asn Asn Lys
660 665 670
Thr
<210> 3
<211> 663
<212> PRT
<213> Artificial Sequence
<220>
<223> DME deltaN687+lnk
<400> 3
Glu Ser Lys Lys Arg Lys Pro Arg Pro Lys Val Asp Ile Asp Asp Glu
1 5 10 15
Thr Thr Arg Ile Trp Asn Leu Leu Met Gly Lys Gly Asp Glu Lys Glu
20 25 30
Gly Asp Glu Glu Lys Asp Lys Lys Lys Glu Lys Trp Trp Glu Glu Glu
35 40 45
Arg Arg Val Phe Arg Gly Arg Ala Asp Ser Phe Ile Ala Arg Met His
50 55 60
Leu Val Gln Gly Asp Arg Arg Phe Ser Pro Trp Lys Gly Ser Val Val
65 70 75 80
Asp Ser Val Ile Gly Val Phe Leu Thr Gln Asn Val Ser Asp His Leu
85 90 95
Ser Ser Ser Ala Phe Met Ser Leu Ala Ala Arg Phe Pro Pro Ala Gly
100 105 110
Ser Ser Gly Asn Gly Ser Ser Gly Asn Gly Thr Ser Gln Trp Asp Ser
115 120 125
Leu Arg Lys Asp Val Glu Gly Asn Glu Gly Arg Gln Glu Arg Asn Lys
130 135 140
Asn Asn Met Asp Ser Ile Asp Tyr Glu Ala Ile Arg Arg Ala Ser Ile
145 150 155 160
Ser Glu Ile Ser Glu Ala Ile Lys Glu Arg Gly Met Asn Asn Met Leu
165 170 175
Ala Val Arg Ile Lys Asp Phe Leu Glu Arg Ile Val Lys Asp His Gly
180 185 190
Gly Ile Asp Leu Glu Trp Leu Arg Glu Ser Pro Pro Asp Lys Ala Lys
195 200 205
Asp Tyr Leu Leu Ser Ile Arg Gly Leu Gly Leu Lys Ser Val Glu Cys
210 215 220
Val Arg Leu Leu Thr Leu His Asn Leu Ala Phe Pro Val Asp Thr Asn
225 230 235 240
Val Gly Arg Ile Ala Val Arg Met Gly Trp Val Pro Leu Gln Pro Leu
245 250 255
Pro Glu Ser Leu Gln Leu His Leu Leu Glu Leu Tyr Pro Val Leu Glu
260 265 270
Ser Ile Gln Lys Phe Leu Trp Pro Arg Leu Cys Lys Leu Asp Gln Arg
275 280 285
Thr Leu Tyr Glu Leu His Tyr Gln Leu Ile Thr Phe Gly Lys Val Phe
290 295 300
Cys Thr Lys Ser Arg Pro Asn Cys Asn Ala Cys Pro Met Arg Gly Glu
305 310 315 320
Cys Arg His Phe Ala Ser Ala Tyr Ala Ser Ala Arg Leu Ala Leu Pro
325 330 335
Ala Pro Glu Glu Arg Ser Leu Thr Ser Ala Thr Ile Pro Val Pro Pro
340 345 350
Glu Ser Phe Pro Pro Val Ala Ile Pro Met Ile Glu Leu Pro Leu Pro
355 360 365
Leu Glu Lys Ser Leu Ala Ser Gly Ala Pro Ser Asn Arg Glu Asn Cys
370 375 380
Glu Pro Ile Ile Glu Glu Pro Ala Ser Pro Gly Gln Glu Cys Thr Glu
385 390 395 400
Ile Thr Glu Ser Asp Ile Glu Asp Ala Tyr Tyr Asn Glu Asp Pro Asp
405 410 415
Glu Ile Pro Thr Ile Lys Leu Asn Ile Glu Gln Phe Gly Met Thr Leu
420 425 430
Arg Glu His Met Glu Arg Asn Met Glu Leu Gln Glu Gly Asp Met Ser
435 440 445
Lys Ala Leu Val Ala Leu His Pro Thr Thr Thr Ser Ile Pro Thr Pro
450 455 460
Lys Leu Lys Asn Ile Ser Arg Leu Arg Thr Glu His Gln Val Tyr Glu
465 470 475 480
Leu Pro Asp Ser His Arg Leu Leu Asp Gly Met Asp Lys Arg Glu Pro
485 490 495
Asp Asp Pro Ser Pro Tyr Leu Leu Ala Ile Trp Thr Pro Gly Glu Thr
500 505 510
Ala Asn Ser Ala Gln Pro Pro Glu Gln Lys Cys Gly Gly Lys Ala Ser
515 520 525
Gly Lys Met Cys Phe Asp Glu Thr Cys Ser Glu Cys Asn Ser Leu Arg
530 535 540
Glu Ala Asn Ser Gln Thr Val Arg Gly Thr Leu Leu Ile Pro Cys Arg
545 550 555 560
Thr Ala Met Arg Gly Ser Phe Pro Leu Asn Gly Thr Tyr Phe Gln Val
565 570 575
Asn Glu Leu Phe Ala Asp His Glu Ser Ser Leu Lys Pro Ile Asp Val
580 585 590
Pro Arg Asp Trp Ile Trp Asp Leu Pro Arg Arg Thr Val Tyr Phe Gly
595 600 605
Thr Ser Val Thr Ser Ile Phe Arg Gly Leu Ser Thr Glu Gln Ile Gln
610 615 620
Phe Cys Phe Trp Lys Gly Phe Val Cys Val Arg Gly Phe Glu Gln Lys
625 630 635 640
Thr Arg Ala Pro Arg Pro Leu Met Ala Arg Leu His Phe Pro Ala Ser
645 650 655
Lys Leu Lys Asn Asn Lys Thr
660
<210> 4
<211> 653
<212> PRT
<213> Artificial Sequence
<220>
<223> DME deltaN697+lnk
<400> 4
Val Asp Ile Asp Asp Glu Thr Thr Arg Ile Trp Asn Leu Leu Met Gly
1 5 10 15
Lys Gly Asp Glu Lys Glu Gly Asp Glu Glu Lys Asp Lys Lys Lys Glu
20 25 30
Lys Trp Trp Glu Glu Glu Arg Arg Val Phe Arg Gly Arg Ala Asp Ser
35 40 45
Phe Ile Ala Arg Met His Leu Val Gln Gly Asp Arg Arg Phe Ser Pro
50 55 60
Trp Lys Gly Ser Val Val Asp Ser Val Ile Gly Val Phe Leu Thr Gln
65 70 75 80
Asn Val Ser Asp His Leu Ser Ser Ser Ala Phe Met Ser Leu Ala Ala
85 90 95
Arg Phe Pro Pro Ala Gly Ser Ser Gly Asn Gly Ser Ser Gly Asn Gly
100 105 110
Thr Ser Gln Trp Asp Ser Leu Arg Lys Asp Val Glu Gly Asn Glu Gly
115 120 125
Arg Gln Glu Arg Asn Lys Asn Asn Met Asp Ser Ile Asp Tyr Glu Ala
130 135 140
Ile Arg Arg Ala Ser Ile Ser Glu Ile Ser Glu Ala Ile Lys Glu Arg
145 150 155 160
Gly Met Asn Asn Met Leu Ala Val Arg Ile Lys Asp Phe Leu Glu Arg
165 170 175
Ile Val Lys Asp His Gly Gly Ile Asp Leu Glu Trp Leu Arg Glu Ser
180 185 190
Pro Pro Asp Lys Ala Lys Asp Tyr Leu Leu Ser Ile Arg Gly Leu Gly
195 200 205
Leu Lys Ser Val Glu Cys Val Arg Leu Leu Thr Leu His Asn Leu Ala
210 215 220
Phe Pro Val Asp Thr Asn Val Gly Arg Ile Ala Val Arg Met Gly Trp
225 230 235 240
Val Pro Leu Gln Pro Leu Pro Glu Ser Leu Gln Leu His Leu Leu Glu
245 250 255
Leu Tyr Pro Val Leu Glu Ser Ile Gln Lys Phe Leu Trp Pro Arg Leu
260 265 270
Cys Lys Leu Asp Gln Arg Thr Leu Tyr Glu Leu His Tyr Gln Leu Ile
275 280 285
Thr Phe Gly Lys Val Phe Cys Thr Lys Ser Arg Pro Asn Cys Asn Ala
290 295 300
Cys Pro Met Arg Gly Glu Cys Arg His Phe Ala Ser Ala Tyr Ala Ser
305 310 315 320
Ala Arg Leu Ala Leu Pro Ala Pro Glu Glu Arg Ser Leu Thr Ser Ala
325 330 335
Thr Ile Pro Val Pro Pro Glu Ser Phe Pro Pro Val Ala Ile Pro Met
340 345 350
Ile Glu Leu Pro Leu Pro Leu Glu Lys Ser Leu Ala Ser Gly Ala Pro
355 360 365
Ser Asn Arg Glu Asn Cys Glu Pro Ile Ile Glu Glu Pro Ala Ser Pro
370 375 380
Gly Gln Glu Cys Thr Glu Ile Thr Glu Ser Asp Ile Glu Asp Ala Tyr
385 390 395 400
Tyr Asn Glu Asp Pro Asp Glu Ile Pro Thr Ile Lys Leu Asn Ile Glu
405 410 415
Gln Phe Gly Met Thr Leu Arg Glu His Met Glu Arg Asn Met Glu Leu
420 425 430
Gln Glu Gly Asp Met Ser Lys Ala Leu Val Ala Leu His Pro Thr Thr
435 440 445
Thr Ser Ile Pro Thr Pro Lys Leu Lys Asn Ile Ser Arg Leu Arg Thr
450 455 460
Glu His Gln Val Tyr Glu Leu Pro Asp Ser His Arg Leu Leu Asp Gly
465 470 475 480
Met Asp Lys Arg Glu Pro Asp Asp Pro Ser Pro Tyr Leu Leu Ala Ile
485 490 495
Trp Thr Pro Gly Glu Thr Ala Asn Ser Ala Gln Pro Pro Glu Gln Lys
500 505 510
Cys Gly Gly Lys Ala Ser Gly Lys Met Cys Phe Asp Glu Thr Cys Ser
515 520 525
Glu Cys Asn Ser Leu Arg Glu Ala Asn Ser Gln Thr Val Arg Gly Thr
530 535 540
Leu Leu Ile Pro Cys Arg Thr Ala Met Arg Gly Ser Phe Pro Leu Asn
545 550 555 560
Gly Thr Tyr Phe Gln Val Asn Glu Leu Phe Ala Asp His Glu Ser Ser
565 570 575
Leu Lys Pro Ile Asp Val Pro Arg Asp Trp Ile Trp Asp Leu Pro Arg
580 585 590
Arg Thr Val Tyr Phe Gly Thr Ser Val Thr Ser Ile Phe Arg Gly Leu
595 600 605
Ser Thr Glu Gln Ile Gln Phe Cys Phe Trp Lys Gly Phe Val Cys Val
610 615 620
Arg Gly Phe Glu Gln Lys Thr Arg Ala Pro Arg Pro Leu Met Ala Arg
625 630 635 640
Leu His Phe Pro Ala Ser Lys Leu Lys Asn Asn Lys Thr
645 650
<210> 5
<211> 647
<212> PRT
<213> Artificial Sequence
<220>
<223> DME deltaN703+lnk
<400> 5
Thr Thr Arg Ile Trp Asn Leu Leu Met Gly Lys Gly Asp Glu Lys Glu
1 5 10 15
Gly Asp Glu Glu Lys Asp Lys Lys Lys Glu Lys Trp Trp Glu Glu Glu
20 25 30
Arg Arg Val Phe Arg Gly Arg Ala Asp Ser Phe Ile Ala Arg Met His
35 40 45
Leu Val Gln Gly Asp Arg Arg Phe Ser Pro Trp Lys Gly Ser Val Val
50 55 60
Asp Ser Val Ile Gly Val Phe Leu Thr Gln Asn Val Ser Asp His Leu
65 70 75 80
Ser Ser Ser Ala Phe Met Ser Leu Ala Ala Arg Phe Pro Pro Ala Gly
85 90 95
Ser Ser Gly Asn Gly Ser Ser Gly Asn Gly Thr Ser Gln Trp Asp Ser
100 105 110
Leu Arg Lys Asp Val Glu Gly Asn Glu Gly Arg Gln Glu Arg Asn Lys
115 120 125
Asn Asn Met Asp Ser Ile Asp Tyr Glu Ala Ile Arg Arg Ala Ser Ile
130 135 140
Ser Glu Ile Ser Glu Ala Ile Lys Glu Arg Gly Met Asn Asn Met Leu
145 150 155 160
Ala Val Arg Ile Lys Asp Phe Leu Glu Arg Ile Val Lys Asp His Gly
165 170 175
Gly Ile Asp Leu Glu Trp Leu Arg Glu Ser Pro Pro Asp Lys Ala Lys
180 185 190
Asp Tyr Leu Leu Ser Ile Arg Gly Leu Gly Leu Lys Ser Val Glu Cys
195 200 205
Val Arg Leu Leu Thr Leu His Asn Leu Ala Phe Pro Val Asp Thr Asn
210 215 220
Val Gly Arg Ile Ala Val Arg Met Gly Trp Val Pro Leu Gln Pro Leu
225 230 235 240
Pro Glu Ser Leu Gln Leu His Leu Leu Glu Leu Tyr Pro Val Leu Glu
245 250 255
Ser Ile Gln Lys Phe Leu Trp Pro Arg Leu Cys Lys Leu Asp Gln Arg
260 265 270
Thr Leu Tyr Glu Leu His Tyr Gln Leu Ile Thr Phe Gly Lys Val Phe
275 280 285
Cys Thr Lys Ser Arg Pro Asn Cys Asn Ala Cys Pro Met Arg Gly Glu
290 295 300
Cys Arg His Phe Ala Ser Ala Tyr Ala Ser Ala Arg Leu Ala Leu Pro
305 310 315 320
Ala Pro Glu Glu Arg Ser Leu Thr Ser Ala Thr Ile Pro Val Pro Pro
325 330 335
Glu Ser Phe Pro Pro Val Ala Ile Pro Met Ile Glu Leu Pro Leu Pro
340 345 350
Leu Glu Lys Ser Leu Ala Ser Gly Ala Pro Ser Asn Arg Glu Asn Cys
355 360 365
Glu Pro Ile Ile Glu Glu Pro Ala Ser Pro Gly Gln Glu Cys Thr Glu
370 375 380
Ile Thr Glu Ser Asp Ile Glu Asp Ala Tyr Tyr Asn Glu Asp Pro Asp
385 390 395 400
Glu Ile Pro Thr Ile Lys Leu Asn Ile Glu Gln Phe Gly Met Thr Leu
405 410 415
Arg Glu His Met Glu Arg Asn Met Glu Leu Gln Glu Gly Asp Met Ser
420 425 430
Lys Ala Leu Val Ala Leu His Pro Thr Thr Thr Ser Ile Pro Thr Pro
435 440 445
Lys Leu Lys Asn Ile Ser Arg Leu Arg Thr Glu His Gln Val Tyr Glu
450 455 460
Leu Pro Asp Ser His Arg Leu Leu Asp Gly Met Asp Lys Arg Glu Pro
465 470 475 480
Asp Asp Pro Ser Pro Tyr Leu Leu Ala Ile Trp Thr Pro Gly Glu Thr
485 490 495
Ala Asn Ser Ala Gln Pro Pro Glu Gln Lys Cys Gly Gly Lys Ala Ser
500 505 510
Gly Lys Met Cys Phe Asp Glu Thr Cys Ser Glu Cys Asn Ser Leu Arg
515 520 525
Glu Ala Asn Ser Gln Thr Val Arg Gly Thr Leu Leu Ile Pro Cys Arg
530 535 540
Thr Ala Met Arg Gly Ser Phe Pro Leu Asn Gly Thr Tyr Phe Gln Val
545 550 555 560
Asn Glu Leu Phe Ala Asp His Glu Ser Ser Leu Lys Pro Ile Asp Val
565 570 575
Pro Arg Asp Trp Ile Trp Asp Leu Pro Arg Arg Thr Val Tyr Phe Gly
580 585 590
Thr Ser Val Thr Ser Ile Phe Arg Gly Leu Ser Thr Glu Gln Ile Gln
595 600 605
Phe Cys Phe Trp Lys Gly Phe Val Cys Val Arg Gly Phe Glu Gln Lys
610 615 620
Thr Arg Ala Pro Arg Pro Leu Met Ala Arg Leu His Phe Pro Ala Ser
625 630 635 640
Lys Leu Lys Asn Asn Lys Thr
645
<210> 6
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> nuclear localization signal
<400> 6
Pro Lys Lys Lys Arg Lys Val Gly Val Asp
1 5 10
<210> 7
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker
<400> 7
Gly Gly Gly Ser
1
<210> 8
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker
<400> 8
Ala Gly Ser Ser Gly Asn Gly Ser Ser Gly Asn Gly
1 5 10
<210> 9
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for Oct4 promoter
<400> 9
gttttggggt tattaagagt tattgaayga ggg 33
<210> 10
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for Oct4 promoter
<400> 10
cccaaaacrc caacrctaca atc 23
<210> 11
<211> 41
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for site directed mutagenesis of Cas9
<400> 11
ccgactacga tgtggacgcc atcgtgcctc agagctttct g 41
<210> 12
<211> 41
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for site directed mutagenesis of Cas9
<400> 12
cagaaagctc tgaggcacga tggcgtccac atcgtagtcg g 41
<210> 13
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for dCas9 fragment
<400> 13
aattacgcgt atggactata aggaccacga cgg 33
<210> 14
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for dCas9 fragment
<400> 14
aattactagt ctttttcttt tttgcctggc cggc 34
<210> 15
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for mutagenesis of DME BbsI site
<400> 15
ggaagaagaa agaagagtct ttcgaggaag ggctgattcc 40
<210> 16
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for mutagenesis of DME BbsI site
<400> 16
ggaatcagcc cttcctcgaa agactcttct ttcttcttcc 40
<210> 17
<211> 38
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for mutagenesis of DME BbsI site
<400> 17
gtccgtggat tcgaacagaa aacaagagca ccgcgtcc 38
<210> 18
<211> 38
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for mutagenesis of DME BbsI site
<400> 18
ggacgcggtg ctcttgtttt ctgttcgaat ccacggac 38
<210> 19
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for mutagenesis of Tet1CD BbsI site
<400> 19
ggcttctcct ggtccccgaa aactgcttca gccacaccag 40
<210> 20
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for mutagenesis of Tet1CD BbsI site
<400> 20
ctggtgtggc tgaagcagtt ttcggggacc aggagaagcc 40
<210> 21
<211> 41
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for mutagenesis of Tet1CD BbsI site
<400> 21
ctgtacgatg ccttcgggaa aactcagtgg tgccaatgca g 41
<210> 22
<211> 41
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for mutagenesis of Tet1CD BbsI site
<400> 22
ctgcattggc accactgagt tttcccgaag gcatcgtaca g 41
<210> 23
<211> 32
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for DME deltaN677+lnk
<400> 23
aattactagt tacaaaggag atggtgcact tg 32
<210> 24
<211> 37
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for DME deltaN677+lnk
<400> 24
aattgtttaa acttaggttt tgttgttctt caatttg 37
<210> 25
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for DME deltaN697+lnk
<400> 25
aattactagt gttgacattg acgatgaaac 30
<210> 26
<211> 37
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for DME deltaN697+lnk
<400> 26
aattgtttaa acttaggttt tgttgttctt caatttg 37
<210> 27
<211> 32
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for TET1 CD
<400> 27
aattactagt gaactgccca cctgcagctg tc 32
<210> 28
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for TET1 CD
<400> 28
aattgtttaa actcagaccc aatggttata gggcc 35
<210> 29
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> Complementary forward primer for RANKL sgRNA
<400> 29
caccgcaagg ggagtctgga accac 25
<210> 30
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> Complementary reverse primer for RANKL sgRNA
<400> 30
aaacgtggtt ccagactccc cttgc 25
<210> 31
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> RANKL target sequence
<400> 31
caaggggagt ctggaaccac 20
<210> 32
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for RANKL
<400> 32
actattaatg ccaccgaca 19
<210> 33
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for RANKL
<400> 33
agggtatgag aacttgggat 20
<210> 34
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for interferon beta
<400> 34
cattacctga aggccaagga 20
<210> 35
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for interferon beta
<400> 35
cagcatctgc tggttgaaga 20
<210> 36
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Forward primer for GAPDH
<400> 36
gagtcaacgg atttggtcgt 20
<210> 37
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Reverse primer for GAPDH
<400> 37
gacaagcttc ccgttctcag 20
Claims (17)
- DNA 탈메틸화 촉매 활성을 갖는 식물 유래 제1 폴리펩티드 및 표적 DNA에 특이적으로 결합하는 제2 폴리펩티드를 포함하는 융합 단백질, 또는 상기 융합 단백질을 암호화하는 폴리뉴클레오티드를 포함하는,
동물 세포에서 표적 DNA의 메틸화를 감소시키기 위한 조성물. - 청구항 1에 있어서, 상기 식물 유래 제1 폴리펩티드는 애기장대(Arabidopsis thaliana) 유래 DNA 탈메틸화효소인 것인 조성물.
- 청구항 1에 있어서, 상기 제1 폴리펩티드는 DEMETER(DME) 또는 이의 변이체인 것인 조성물.
- 청구항 3에 있어서, 상기 DEMETER 변이체는 서열번호 1의 DME의 아미노산 서열에서 N-말단으로부터 1 내지 677번째 아미노산 서열, 1 내지 687번째 아미노산 서열, 1 내지 697번째 아미노산 서열, 또는 1 내지 703번째 아미노산 서열이 결실(deletion)된 것인 조성물.
- 청구항 3에 있어서, 상기 DEMETER 변이체는 서열번호 2 내지 5로 이루어진 군으로부터 선택된 아미노산 서열로 이루어진 것인 조성물.
- 청구항 1에 있어서, 상기 제1 폴리펩티드는 DNA로부터 메틸화된 시토신을 절제하는 탈메틸화효소인 것인 조성물.
- 청구항 1에 있어서, 상기 제2 폴리펩티드는 TALE(Transcription Activator Like Effector) 폴리펩티드, Cas 폴리펩티드, 전사인자, 및 징크-핑거 뉴클레아제(Zinc-finger nuclease: ZFN)의 DNA-결합 도메인으로 이루어진 군으로부터 선택된 것인 조성물.
- 청구항 1에 있어서, 상기 Cas 폴리펩티드는 Cas9 폴리펩티드인 것인 조성물.
- 청구항 1에 있어서, 상기 Cas9 폴리펩티드는 야생형 Cas9, 틈내기효소 Cas9(nickase Cas9: nCas9), 및 촉매활성이 없는 Cas9(catalytically dead Cas9: dCas9)으로 이루어진 군으로부터 선택된 것인 조성물.
- 청구항 1에 있어서, 상기 융합 단백질은 형광 단백질, 핵 위치 신호(nuclear localization signal: NLS), 링커 아미노산 서열, 또는 이들의 조합을 더 포함하는 것인 조성물.
- 청구항 1에 있어서, 상기 융합 단백질은 그의 N-말단으로부터 제2 폴리펩티드 및 제1 폴리펩티드의 순서로 연결된 것인 조성물.
- 청구항 1에 있어서, 상기 폴리뉴클레오티드는 표적 DNA에 상보적으로 결합할 수 있는 단일 가이드 RNA(single guide RNA: sgRNA), 프로모터, 폴리-아데노신(poly-adenosine: poly(A)) 서열, 또는 이들의 조합을 더 포함하는 것인 조성물.
- 청구항 1에 있어서, 상기 동물 세포는 인간, 소, 말, 돼지, 개, 양, 염소, 고양이, 또는 마우스로부터 유래된 세포인 것인 조성물.
- 청구항 1에 있어서, 상기 조성물은 시험관 내(in vitro), 생체 내(in vivo), 또는 생체 외(ex vivo) 투여용인 것인 조성물.
- DNA 탈메틸화 촉매 활성을 갖는 식물 유래 제1 폴리펩티드 및 표적 DNA에 특이적으로 결합하는 제2 폴리펩티드를 포함하는 융합 단백질, 또는 상기 융합 단백질을 암호화하는 폴리뉴클레오티드를 포함하는,
동물 세포에서 표적 DNA의 메틸화를 감소시키기 위한 키트. - DNA 탈메틸화 촉매 활성을 갖는 식물 유래 제1 폴리펩티드 및 표적 DNA에 특이적으로 결합하는 제2 폴리펩티드를 포함하는 융합 단백질을 암호화하는 폴리뉴클레오티드와 동물 세포를 인큐베이션시켜 상기 폴리뉴클레오티드를 동물 세포에 도입하는 단계를 포함하는,
동물 세포에서 표적 DNA를 탈메틸화시키는 방법. - 청구항 16에 있어서, 상기 방법은 동물 세포에 표적 DNA를 탈메틸화시킴으로써 표적 유전자의 발현을 유도하는 것인 방법.
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WO2021169925A1 (zh) * | 2020-02-26 | 2021-09-02 | 山东舜丰生物科技有限公司 | 一种融合蛋白及其应用 |
WO2023108929A1 (zh) * | 2022-01-17 | 2023-06-22 | 广州医科大学 | 靶向dna去甲基化的方法、融合蛋白及其应用 |
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WO2021169925A1 (zh) * | 2020-02-26 | 2021-09-02 | 山东舜丰生物科技有限公司 | 一种融合蛋白及其应用 |
WO2023108929A1 (zh) * | 2022-01-17 | 2023-06-22 | 广州医科大学 | 靶向dna去甲基化的方法、融合蛋白及其应用 |
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