Science：中国学者采用成年早衰症干细胞模型揭示衰老的分子机制

2015-05-02 MedSci MedSci原创

2015年4月30日，Science杂志在线发表了北京大学生命科学学院生物动态光学成像中心汤富酬实验室、中科院生物物理所刘光慧实验室、以及Salk研究所Juan Carlos Izpisua Belmonte实验室在干细胞衰老机理方面的一项突破性的研究成果。该研究结合多能干细胞定向分化技术、基因组靶向编辑技术、以及表观遗传组分析技术首次揭示了异染色质的高级结构失序(disorganizat

2015年4月30日，Science杂志在线发表了北京大学生命科学学院生物动态光学成像中心汤富酬实验室、中科院生物物理所刘光慧实验室、以及Salk研究所Juan Carlos Izpisua Belmonte实验室在干细胞衰老机理方面的一项突破性的研究成果。该研究结合多能干细胞定向分化技术、基因组靶向编辑技术、以及表观遗传组分析技术首次揭示了异染色质的高级结构失序(disorganization)是人类干细胞衰老的驱动力之一，为延缓衰老及研究和防治衰老相关疾病提供了新的潜在靶点和思路。

20150501095231_577026_21766

描述WRN保护异染色质稳定性的示意图

目前世界各国均面临着严重的人口老龄化，2050年约三分之一的中国人口年龄将超过60岁。衰老是人类疾病最大的危险因子，针对衰老的基础和转化医学研究正成为全人类共同关注且亟需解决的重大科学问题。然而，人类衰老的过程漫长且复杂，小鼠等模式动物的衰老过程与人相差甚远，人类衰老的转化医学研究一直面临着巨大的挑战。成年早衰症(Werner Syndrome)是一种罕见的常染色体隐性遗传病，由WRN基因(编码一种DNA修复/解旋酶)的突变所致。成年早衰症患者自青春期开始提前启动衰老程序，加速呈现出自然衰老的表征并伴发多种老年性疾病。因此，研究成年早衰症对于揭示人类自然衰老的奥秘以及实现防治衰老相关疾病具有重要的科学意义。

20150501095401_334160_27064

表观遗传组学分析显示，早衰症干细胞的异染色质发生了显著的结构退行性变化，主要表现为着丝粒和端粒附近的H3K9me3“山脉”(mountains)的缺失

研究人员首先提出“组织干细胞的加速衰老(耗竭)可能是成年早衰症的病因”这一科学假设，并通过基因组靶向编辑技术使得人间充质干细胞(MSC)中的WRN基因发生纯合缺失突变，在实验室创造出人类早衰症特异的MSC。这些早衰症MSC不仅表现出生长速度减慢、DNA损伤反应加剧和分泌大量炎性因子等衰老指征，而且表现出内层核膜蛋白以及核周异染色质的加速缺失。通过对组蛋白共价修饰、DNA甲基化、以及RNA转录本进行全基因组扫描，研究人员发现早衰症干细胞的异染色质发生了显著的结构退行性变化，主要表现为着丝粒和端粒附近的H3K9me3“山脉”(mountains)的缺失。进一步研究发现，WRN蛋白同异染色质蛋白SUV39H1和HP1共存于一个蛋白复合物中，该复合物具有维持异染色质和核纤层的稳定性以及阻止MSC衰老的作用。WRN的缺失导致异染色质结合蛋白的减少以及着丝粒卫星DNA的转录，进而诱发细胞衰老。通过比较健康老年人和年轻人体内分离的MSC，也可见WRN水平的下调以及核膜蛋白和异染色质结构的异常，提示异染色质的重塑可能是正常细胞衰老的驱动力之一。最后，研究发现过量表达HP1能抑制早衰症细胞的加速衰老，因而为未来干预人类干细胞的衰老提供了可能的分子靶标。

人们普遍认为，衰老来源于细胞内不断聚集的DNA损伤(基因组不稳定性)。作为支持该理论的重要依据之一：DNA损伤修复蛋白WRN的突变会导致人类成年早衰症。此项研究首次利用人类成年早衰症的干细胞模型，揭示了WRN蛋白在维持异染色质稳定性方面的全新功能，阐明了染色质的高级结构失序在细胞衰老中发挥的驱动性作用，并由此提出人类干细胞衰老可能归因于表观遗传改变和基因组不稳定性的互作。

研究人员发现删除WRN基因可导致异染色质解体，指出了WRN蛋白在维持异染色质中起重要作用。确实在进一步的实验中，他们证实这一蛋白直接与一些已知稳定异染色质的分子结构发生了直接互作，第一次揭示了直接连接突变WRN蛋白和异染色质解体的确凿证据。

Izpisua Belmonte说：“我们的研究将Werner综合征和异染色质解体联系起来，描绘了一种遗传突变通过破坏表观遗传调控导致一些细胞过程普遍遭到破坏的分子机制。更广泛地说，它表明了异染色质结构中累积的改变有可能是细胞衰老的一个主要潜在原因。这引发了一个问题：我们是否可以像重塑老房子或汽车一样逆转这些改变，来防止或甚至逆转年龄相关的衰退和疾病。”

Izpisua Belmonte补充说，还需要更广泛的研究来充分了解异染色质解体在衰老中的作用，包括它是如何与衰老中一些相关的细胞过程例如端粒缩短发生互作的。此外，Izpisua Belmonte研究小组正在开发一些表观遗传编辑技术来逆转在人类衰老和疾病中起作用的一些表观遗传改变。

此项工作由中科院生物物理所、北京大学、中科院动物所、解放军306医院、深圳大学以及Salk研究所等科研机构合作完成。中科院生物物理所刘光慧研究员、北京大学生命科学学院生物动态光学成像中心汤富酬研究员、以及Salk研究所Juan Carlos Izpisua Belmonte教授为该论文的共同通讯作者。中科院生物物理所助理研究员张维绮、北京大学博士研究生李静宜、Salk研究所博士后Keiichiro Suzuki以及中科院动物所研究员曲静为本文的并列第一作者。此项研究受到国家自然科学基金委、科技部973计划、中科院干细胞与再生医学战略先导专项、以及北大清华联合中心的资助。

原始出处：

Weiqi Zhang, Jingyi Li, Keiichiro Suzuki, Jing Qu, Ping Wang, Junzhi Zhou, Xiaomeng Liu, Ruotong Ren, Xiuling Xu, Alejandro Ocampo, Tingting Yuan, Jiping Yang, Ying Li, Liang Shi, Dee Guan, Huize Pan, Shunlei Duan, Zhichao Ding, Mo Li, Fei Yi, Ruijun Bai, Yayu Wang, Chang Chen, Fuquan Yang, Xiaoyu Li, Zimei Wang, Emi Aizawa, April Goebl, Rupa Devi Soligalla, Pradeep Reddy, Concepcion Rodriguez Esteban, Fuchou Tang, Guang-Hui Liu, Juan Carlos Izpisua Belmonte. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.Science DOI: 10.1126/science.aaa1356

作者简介

刘光慧研究员

1997-2002 北京大学医学部，药理学学士

2002-2007 中国科学院生物物理研究所，理学博士

2007-2009 美国斯科利普斯(Scripps)研究所 Research associate

2009-2011 美国索尔克(Salk)生物学研究所 Research associate

2011-今　中科院生物物理研究所，研究员，博士生导师

2012年　入选中国国家青年***计划

研究组工作摘要：

1. 基于多能干细胞(PSCs;包括iPSC和ESCs)的人类疾病模型、药物筛选系统和治疗体系

利用病人诱导性多能干细胞（iPSC）和体外创建的“病人”胚胎干细胞（ESC），结合定向分化和细胞移植技术，在功能基因组水平研究人类疾病的分子机理及新型靶标；发展基于干细胞技术的药物筛选和评价体系；探索利用自体干细胞进行个体化治疗的可行性。

2. 人类健康长寿（healthy aging）的分子遗传学基础

结合干细胞和基因组靶向修饰技术，研究人类衰老和老年病的细胞分子机理和遗传学基础，探索延缓衰老和防治老年病的方法和手段，以期实现“健康长寿”的梦想。

汤富酬

2003年在北京大学获理学博士学位，2004－2010年，英国剑桥大学Gurdon研究所博士后，2010年至今在北京大学生物动态光学成像中心任研究员。主要围绕哺乳动物早期胚胎发育，研究胚胎干细胞和上胚层干细胞的自我更新能力和多能性调控的分子机理，特别是表观遗传学调控机理，以及相关的原始生殖细胞发育过程中的表观遗传学重编程机理。利用本实验室发展的单细胞microRNA表达谱分析技术、基于深度测序的单细胞数字转录组分析技术、单细胞基因分型技术、以及染色体免疫共沉淀-深度测序技术、小鼠胚胎显微操作技术深入分析多能性干细胞的动态基因表达网络和表观遗传学调控。

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2015-10-14 yeaweam

#细胞模型#

26 0
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2015-05-04 jichang

#SCIE#

36 0
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2015-05-04 zhangfenasdf

#早衰症#

35 0
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2015-05-03 acount

什么时候才能看到真正的产出

134 0
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2015-05-03 203.190.121.**

HGH

115 0
[GetPortalCommentsPageByObjectIdResponse(id=1805351, encodeId=8e271805351df, content=<a href='/topic/show?id=e078e79331a' target=_blank style='color:#2F92EE;'>#细胞模型#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77933, encryptionId=e078e79331a, topicName=细胞模型)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=21e5394, createdName=yeaweam, createdTime=Wed Oct 14 02:56:00 CST 2015, time=2015-10-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1375031, encodeId=c7dd13e50314f, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Mon May 04 02:56:00 CST 2015, time=2015-05-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1530833, encodeId=929115308337f, content=<a href='/topic/show?id=f9cd5950630' target=_blank style='color:#2F92EE;'>#早衰症#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=59506, encryptionId=f9cd5950630, topicName=早衰症)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ea8212147736, createdName=zhangfenasdf, createdTime=Mon May 04 02:56:00 CST 2015, time=2015-05-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22538, encodeId=733722538f9, content=什么时候才能看到真正的产出, beContent=null, objectType=article, channel=null, level=null, likeNumber=134, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=acount, createdTime=Sun May 03 20:17:00 CST 2015, time=2015-05-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22513, encodeId=a65e2251355, content=HGH, beContent=null, objectType=article, channel=null, level=null, likeNumber=115, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=203.190.121.**, createdTime=Sun May 03 11:38:00 CST 2015, time=2015-05-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22502, encodeId=bf66225024a, content=期待, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=121e1622385, createdName=chenhui888, createdTime=Sun May 03 09:46:00 CST 2015, time=2015-05-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22433, encodeId=edc6224336a, content=偶像，学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=122, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ee0d1618732, createdName=huaxipanxing, createdTime=Sat May 02 19:44:00 CST 2015, time=2015-05-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22432, encodeId=86f022432f4, content=哦, beContent=null, objectType=article, channel=null, level=null, likeNumber=121, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=93c31615857, createdName=elisahuang, createdTime=Sat May 02 16:43:00 CST 2015, time=2015-05-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22428, encodeId=b59222428b4, content=人类以后长寿了, beContent=null, objectType=article, channel=null, level=null, likeNumber=75, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=hbwang006, createdTime=Sat May 02 13:40:00 CST 2015, time=2015-05-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22420, encodeId=e7f72242083, content=厉害!, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=96871613250, createdName=medcardio, createdTime=Sat May 02 12:17:00 CST 2015, time=2015-05-02, status=1, ipAttribution=)]
2015-05-03 chenhui888

期待

82 0
[GetPortalCommentsPageByObjectIdResponse(id=1805351, encodeId=8e271805351df, content=<a href='/topic/show?id=e078e79331a' target=_blank style='color:#2F92EE;'>#细胞模型#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77933, encryptionId=e078e79331a, topicName=细胞模型)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=21e5394, createdName=yeaweam, createdTime=Wed Oct 14 02:56:00 CST 2015, time=2015-10-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1375031, encodeId=c7dd13e50314f, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Mon May 04 02:56:00 CST 2015, time=2015-05-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1530833, encodeId=929115308337f, content=<a href='/topic/show?id=f9cd5950630' target=_blank style='color:#2F92EE;'>#早衰症#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=59506, encryptionId=f9cd5950630, topicName=早衰症)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ea8212147736, createdName=zhangfenasdf, createdTime=Mon May 04 02:56:00 CST 2015, time=2015-05-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22538, encodeId=733722538f9, content=什么时候才能看到真正的产出, beContent=null, objectType=article, channel=null, level=null, likeNumber=134, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=acount, createdTime=Sun May 03 20:17:00 CST 2015, time=2015-05-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22513, encodeId=a65e2251355, content=HGH, beContent=null, objectType=article, channel=null, level=null, likeNumber=115, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=203.190.121.**, createdTime=Sun May 03 11:38:00 CST 2015, time=2015-05-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22502, encodeId=bf66225024a, content=期待, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=121e1622385, createdName=chenhui888, createdTime=Sun May 03 09:46:00 CST 2015, time=2015-05-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22433, encodeId=edc6224336a, content=偶像，学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=122, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ee0d1618732, createdName=huaxipanxing, createdTime=Sat May 02 19:44:00 CST 2015, time=2015-05-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22432, encodeId=86f022432f4, content=哦, beContent=null, objectType=article, channel=null, level=null, likeNumber=121, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=93c31615857, createdName=elisahuang, createdTime=Sat May 02 16:43:00 CST 2015, time=2015-05-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22428, encodeId=b59222428b4, content=人类以后长寿了, beContent=null, objectType=article, channel=null, level=null, likeNumber=75, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=hbwang006, createdTime=Sat May 02 13:40:00 CST 2015, time=2015-05-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=22420, encodeId=e7f72242083, content=厉害!, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=96871613250, createdName=medcardio, createdTime=Sat May 02 12:17:00 CST 2015, time=2015-05-02, status=1, ipAttribution=)]
2015-05-02 huaxipanxing

偶像，学习

122 0
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2015-05-02 elisahuang

哦

121 0
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2015-05-02 hbwang006

人类以后长寿了

75 0
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2015-05-02 medcardio

厉害!

80 0

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