癌生物学课件-非编码RNA与肿瘤发生发展
合集下载
相关主题
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
➢ Early 2000s: Large scale cDNA sequencing leads to the discovery of a surprising number of lncRNA trancscripts;
➢ 2000s-Now: The number of predicted protein coding genes in human goes down and the number of detected lncRNA transcripts increases.
↗ Small RNA molecules regulate gene expression by post-transcriptional gene silencing.
↗ Xist: the first long non-coding RNA regulating gene expression.
3. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science. 2014 Apr 18;344(6181):310-3. PMID: 24744378 ；
4. Pubmed关键词： 肿瘤 类型+ lncRNA
(Lagos-Quintana, et al; Lau, et al; Lee, et al. Science)
http://www.mirbase.org/index.shtml (miRBase Sanger Center)
Release 21: June, 2014
miRNA count: 28645 entries 35828 mature miRNAs in 223 species
>70% 被转录 < 2%转录后表达蛋白 (mRNA)
组成型非编码RNA
rRNA，tRNA，snRNA，snoRNA
© dkfz.de
调控型非编码RNA
微小非编码RNA microRNA, siRNA, piRNA, etc
长非编码RNA
Long non-coding RNAs (LncRNAs)
环状RNA
Circular RNA (circRNAs)
6
Non-coding RNAs and Cancer
Oncogenic and Tumor suppressive ncRNAs
Douglas Hanahan and Robert A. Weinberg, Cell 144, 2011: 646-674. 7
10
Biogenesis and Action of microRNAs
11
MicroRNA-mRNA complex interplay
MicroRNAs can regulate about ~60% of all mRNAs!
One miRNA targets multiple mRNAs
↗ Non-coding RNAs control epigenetic phenomena.
…
5 http://www.mfpl.ac.at/rna-biology/rna-history/
Non-coding RNAs in Human Genome
人类基因组蕴藏着数目巨大的非编码RNA
人类基因组（30亿碱基对）
Nature Cell Biology
miR-210 Hepatology
miR-195, Hepatology miR-194, Science Signaling
miR-30d, Hepatology
13
MicroRNA领域值得关注的几个问题
1. microRNA生物合成及表达调控机制； 2. microRNA在疾病进程中的作用及调控网络；（疾病模 型） 3. microRNA在生理、病理中的调节作用；（KO，TG） 4. microRNA转化医学研究：血清诊断、预后判断、分子分型、治疗探索等
14
Contents
➢ Small RNAs (microRNAs); ➢ Long non-coding RNAs (lncRNAs); ➢ Circular RNAs (circRNAs).
15
LncRNA Discovery
LncRNA是一类转录本长度超过200nt的RNA分子
➢ 1980s-1990s: Individual lncRNAs (eg, Xist and H19) are discovered through traditional gene mapping approaches;
LncRNA具复杂的二级与高级 结构，决定其分子调控多样性 Nat Rev Genet. 2014 Jan;15(1):7-21.
17
LncRNA功能和作用机制
LncRNA具有重要分子调节功能，而不是“转录的噪音”
Models of nuclear lncRNA function
Models of cytoplasmic lncRNA function
27
Contents
➢ Small RNAs (microRNAs); ➢ Long non-coding RNAs (lncRNAs); ➢ Circular RNAs (circRNAs).
28
Circular RNA
Circular RNA (circRNA) is a type of RNA that, unlike linear RNA, forms a covalently closed continuous loop.
Biochim Biophys Acta. 2014;1839(11):1097-109.
19
20
HOX lincRNAs are systematically dysregulated in breast cancer
The lincRNA HOTAIR is increased in expression in primary breast tumours and metastases
非编码RNA与肿瘤发生发展
《癌生物学》
Nicolle Rager Fuller
An artist's conception shows an RNA molecule, which may have served as an early form of life on Earth.
2
LUCA： Last Universal Common Ancestor
HOTAIR has prognostic value for metastasis and survival
HOTAIR promotes invasion of breast carcinoma cells.
HOTAIR promotes metastasis of breast carcinoma cells.
The RNA World, 4th edition
1993
1999
Edited By Raymond F. Gesteland Thomas R. Cech John F. Atkins
2006
Cold Spring Harbor Laboratory (CSHL) Press
2010
4
Regulatory RNAs
One mRNA by multiple miRNAs
12
MicroRNA Regulation of Cancer Biology
miR-423 Carcinogenesis
miR-124
Gastroentolgoy
miR-199
Hepatology
miR-125b, Hepatology
miR-151
cytoplasm of eukaryotic cells. Nature 280: 339–340.
...
拓展 （1990s）
Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, et al. (1991) Scrambled exons.
Cell 64: 607–613.
Exonic Circular RNA (circRNAs,环状RNA)
~100,000 circRNAs in human
Wilusz and Sharp, Science, 2013
29
History of circular RNA
发现 （1976）
H.L. Sanger, G. Klotz, D. Riesner, H.J. Gross, A.K. Kleinschmidt.(1976)Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc. Natl. Acad. Sci. USA, 73 pp. 3852–3856. Coca-Prados, M-THaM. (1979) Electron microscopic evidence for the circular form of RNA in the
LncRNA 30344
mRNA
19881
sncRNA 9534
GENECODE V21
16Leabharlann Baidu
LncRNA分类和特征
根据基因组位置分为5类：
双重活性：
可结合蛋白与核酸（RNA,DNA）
Sense, Antisense, Intronic, Intergenic, Bidirectional
Trends Genet. 2014 Oct;30(10):439-52.
The mechanism of HOTAIR in breast cancer progression
LncRNA参考文献
1. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010 Apr 15;464(7291):1071-6. PMID: 20393566；
Homo sapiens ：1,881 precursor (2,588)
9
microRNA:由19-25个核苷酸组成的非编码小分子RNA
DNA
pri-miRNA
microRNA
转录
Cap
加工
AAAAAAAAAA
DNA
Exon Intron
转录
Cap
mRNA
ATG
TGA
翻译
AAAAAAAAAA
Protein
2. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell. 2014 Sep 8;26(3):344-57. PMID: 25203321
Capel B, Swain A, Nicolis S, Hacker A, Walter M, et al. (1993) Circular transcripts of the
染色质重塑 表观遗传修饰 基因转录 可变剪接
mRNA稳定性 mRNA翻译 miRNA sponge 蛋白稳定性/修饰
Nat Rev Genet. 2014 Jan;15(1):7-21.
18
LncRNA与癌症密切相关
Oncogenic and Tumor suppressive lncRNAs
Contents
➢ Small RNAs (microRNAs); ➢ Long non-coding RNAs (lncRNAs); ➢ Circular RNAs (circRNAs).
8
MicroRNA discovery
1993年，第一个miRNA基因——lin-4 (秀丽线虫) (Lee, et al. Cell, 1993, 75:843-854) 2000年，第二个miRNA基因——let-7 (秀丽线虫) (Reinhart, et al. Nature, 2000, 403: 901-6) 2001年，德、美等三个实验室发现约100个miRNA基因 (果蝇、线虫以及人类等)
➢ 2000s-Now: The number of predicted protein coding genes in human goes down and the number of detected lncRNA transcripts increases.
↗ Small RNA molecules regulate gene expression by post-transcriptional gene silencing.
↗ Xist: the first long non-coding RNA regulating gene expression.
3. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science. 2014 Apr 18;344(6181):310-3. PMID: 24744378 ；
4. Pubmed关键词： 肿瘤 类型+ lncRNA
(Lagos-Quintana, et al; Lau, et al; Lee, et al. Science)
http://www.mirbase.org/index.shtml (miRBase Sanger Center)
Release 21: June, 2014
miRNA count: 28645 entries 35828 mature miRNAs in 223 species
>70% 被转录 < 2%转录后表达蛋白 (mRNA)
组成型非编码RNA
rRNA，tRNA，snRNA，snoRNA
© dkfz.de
调控型非编码RNA
微小非编码RNA microRNA, siRNA, piRNA, etc
长非编码RNA
Long non-coding RNAs (LncRNAs)
环状RNA
Circular RNA (circRNAs)
6
Non-coding RNAs and Cancer
Oncogenic and Tumor suppressive ncRNAs
Douglas Hanahan and Robert A. Weinberg, Cell 144, 2011: 646-674. 7
10
Biogenesis and Action of microRNAs
11
MicroRNA-mRNA complex interplay
MicroRNAs can regulate about ~60% of all mRNAs!
One miRNA targets multiple mRNAs
↗ Non-coding RNAs control epigenetic phenomena.
…
5 http://www.mfpl.ac.at/rna-biology/rna-history/
Non-coding RNAs in Human Genome
人类基因组蕴藏着数目巨大的非编码RNA
人类基因组（30亿碱基对）
Nature Cell Biology
miR-210 Hepatology
miR-195, Hepatology miR-194, Science Signaling
miR-30d, Hepatology
13
MicroRNA领域值得关注的几个问题
1. microRNA生物合成及表达调控机制； 2. microRNA在疾病进程中的作用及调控网络；（疾病模 型） 3. microRNA在生理、病理中的调节作用；（KO，TG） 4. microRNA转化医学研究：血清诊断、预后判断、分子分型、治疗探索等
14
Contents
➢ Small RNAs (microRNAs); ➢ Long non-coding RNAs (lncRNAs); ➢ Circular RNAs (circRNAs).
15
LncRNA Discovery
LncRNA是一类转录本长度超过200nt的RNA分子
➢ 1980s-1990s: Individual lncRNAs (eg, Xist and H19) are discovered through traditional gene mapping approaches;
LncRNA具复杂的二级与高级 结构，决定其分子调控多样性 Nat Rev Genet. 2014 Jan;15(1):7-21.
17
LncRNA功能和作用机制
LncRNA具有重要分子调节功能，而不是“转录的噪音”
Models of nuclear lncRNA function
Models of cytoplasmic lncRNA function
27
Contents
➢ Small RNAs (microRNAs); ➢ Long non-coding RNAs (lncRNAs); ➢ Circular RNAs (circRNAs).
28
Circular RNA
Circular RNA (circRNA) is a type of RNA that, unlike linear RNA, forms a covalently closed continuous loop.
Biochim Biophys Acta. 2014;1839(11):1097-109.
19
20
HOX lincRNAs are systematically dysregulated in breast cancer
The lincRNA HOTAIR is increased in expression in primary breast tumours and metastases
非编码RNA与肿瘤发生发展
《癌生物学》
Nicolle Rager Fuller
An artist's conception shows an RNA molecule, which may have served as an early form of life on Earth.
2
LUCA： Last Universal Common Ancestor
HOTAIR has prognostic value for metastasis and survival
HOTAIR promotes invasion of breast carcinoma cells.
HOTAIR promotes metastasis of breast carcinoma cells.
The RNA World, 4th edition
1993
1999
Edited By Raymond F. Gesteland Thomas R. Cech John F. Atkins
2006
Cold Spring Harbor Laboratory (CSHL) Press
2010
4
Regulatory RNAs
One mRNA by multiple miRNAs
12
MicroRNA Regulation of Cancer Biology
miR-423 Carcinogenesis
miR-124
Gastroentolgoy
miR-199
Hepatology
miR-125b, Hepatology
miR-151
cytoplasm of eukaryotic cells. Nature 280: 339–340.
...
拓展 （1990s）
Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, et al. (1991) Scrambled exons.
Cell 64: 607–613.
Exonic Circular RNA (circRNAs,环状RNA)
~100,000 circRNAs in human
Wilusz and Sharp, Science, 2013
29
History of circular RNA
发现 （1976）
H.L. Sanger, G. Klotz, D. Riesner, H.J. Gross, A.K. Kleinschmidt.(1976)Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc. Natl. Acad. Sci. USA, 73 pp. 3852–3856. Coca-Prados, M-THaM. (1979) Electron microscopic evidence for the circular form of RNA in the
LncRNA 30344
mRNA
19881
sncRNA 9534
GENECODE V21
16Leabharlann Baidu
LncRNA分类和特征
根据基因组位置分为5类：
双重活性：
可结合蛋白与核酸（RNA,DNA）
Sense, Antisense, Intronic, Intergenic, Bidirectional
Trends Genet. 2014 Oct;30(10):439-52.
The mechanism of HOTAIR in breast cancer progression
LncRNA参考文献
1. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010 Apr 15;464(7291):1071-6. PMID: 20393566；
Homo sapiens ：1,881 precursor (2,588)
9
microRNA:由19-25个核苷酸组成的非编码小分子RNA
DNA
pri-miRNA
microRNA
转录
Cap
加工
AAAAAAAAAA
DNA
Exon Intron
转录
Cap
mRNA
ATG
TGA
翻译
AAAAAAAAAA
Protein
2. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell. 2014 Sep 8;26(3):344-57. PMID: 25203321
Capel B, Swain A, Nicolis S, Hacker A, Walter M, et al. (1993) Circular transcripts of the
染色质重塑 表观遗传修饰 基因转录 可变剪接
mRNA稳定性 mRNA翻译 miRNA sponge 蛋白稳定性/修饰
Nat Rev Genet. 2014 Jan;15(1):7-21.
18
LncRNA与癌症密切相关
Oncogenic and Tumor suppressive lncRNAs
Contents
➢ Small RNAs (microRNAs); ➢ Long non-coding RNAs (lncRNAs); ➢ Circular RNAs (circRNAs).
8
MicroRNA discovery
1993年，第一个miRNA基因——lin-4 (秀丽线虫) (Lee, et al. Cell, 1993, 75:843-854) 2000年，第二个miRNA基因——let-7 (秀丽线虫) (Reinhart, et al. Nature, 2000, 403: 901-6) 2001年，德、美等三个实验室发现约100个miRNA基因 (果蝇、线虫以及人类等)