Epigenetics A Symphonic Example Epigenetic differences monozygotic twins

Epigenetic differences： monozygotic twins

基因组印记 • Genomic Imprinting: 两条染色体需要随机沉默其一 • Beckwith-Wiedemann Syndrome: 1/15, 000 • BWS： 20%的致死率

2. 基因转录后的调控 • 1. 非编码RNA: e. g. , Xist and Tsix • 2. Micro.

C –> 5 m. C –> T? ? 5 -Methylcytosine (5 m. C)

DEAMINATION • Deamination: 去氨基化反应 An enzyme to remove it from DNA: uracil-Nglycosylase.

DNA甲基化的检测 • 1. 传统实验方法 – Methylation-sensitive restriction enzymes – Methylation-specific enzyme Mcr. BC •

真核生物的DNA甲基转移酶 • 1. 哺乳动物: DNMT 1, DNMT 3 A, DNMT 3 B， DNMT 3

DNA甲基转移酶的功能 DNA甲基转移酶 DNMT 1 DNMT 3 A DNMT 3 B DNMT 3 L

DNA去甲基化 • 1. DNA去甲基化 (DNA demethylation): 5甲基胞嘧啶 (5 m. C) 替代成胞嘧啶的过程 • 2.

组蛋白修饰 Adapted from Lund and Lohuizen Genes Dev 2004

Lysine Methylation • 1. Mono-, di- or tri- methylation • 2. H 3 K

Histone Modification Status Correlates with Transcriptional Activity • Gene activation correlated with H 3

组蛋白密码 • Histone code: The histone code hypothesis predicts that the post-translational modifications of

六、国际人类表观基因组计划 • 1. The Human Genome Project: provides the blueprint for life, but the

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表观遗传学 Epigenetics

A Symphonic Example

Epigenetic differences： monozygotic twins

Waddington's epigenetics 基因型表型

基因组印记 • Genomic Imprinting: 两条染色体需要随机沉默其一 • Beckwith-Wiedemann Syndrome: 1/15, 000 • BWS： 20%的致死率 • BWS: embryonic tumor

2. 基因转录后的调控 • 1. 非编码RNA: e. g. , Xist and Tsix • 2. Micro. RNA • 3. Antisense • 4. Riboswitch RNAs

C –> 5 m. C –> T? ? 5 -Methylcytosine (5 m. C)

DEAMINATION • Deamination: 去氨基化反应 An enzyme to remove it from DNA: uracil-Nglycosylase.

DNA甲基化的检测 • 1. 传统实验方法 – Methylation-sensitive restriction enzymes – Methylation-specific enzyme Mcr. BC • 2. 现代方法 – Me. DIP: methylated DNA immunoprecipitation assay – MBD：methylation binding domain • 3. DNA甲基化位点的确定：Bisulfite genomic sequencing

DNA甲基化抑制基因转录的机制 Long-term silencing

真核生物的DNA甲基转移酶 • 1. 哺乳动物: DNMT 1, DNMT 3 A, DNMT 3 B， DNMT 3 L, DNMT 2 • 2. 拟南芥：DRM 2, MET 1，DNMT 2, CMT 3 • 3. 粗糙脉孢菌 (Neurospora crassa): DIM 2, dim 5, RID

DNA甲基转移酶的功能 DNA甲基转移酶 DNMT 1 DNMT 3 A DNMT 3 B DNMT 3 L DNMT 2 DRM 2 MET 1 DNMT 2 CMT 3 DIM 2 RID 物种主要功能哺乳动物 Maintenance，de novo (Cp. G) 哺乳动物拟南芥拟南芥粗糙脉孢菌 de novo (Cp. G) DNMT 3辅助因子，无活性中心 t. RNAAsp的甲基化 de novo (Cp. N) Maintenance (Cp. G) 未知 Maintenance (Cp. Np. G) de novo (Cp. N) RIP 必须

DNA甲基化：Cell Memory

DNA去甲基化 • 1. DNA去甲基化 (DNA demethylation): 5甲基胞嘧啶 (5 m. C) 替代成胞嘧啶的过程 • 2. 两种方式 – (1) 主动去甲基化 (Active DNA demethylation) • A. Bona fide demethylation • B. Indirect demethylation – (2) 复制相关的去甲基化 (Replication-coupled DNA demethylation)

Histone variants

组蛋白修饰 Adapted from Lund and Lohuizen Genes Dev 2004

HDACs（Histone deacetylases)

Lysine Methylation • 1. Mono-, di- or trimethylation • 2. H 3 K 9 & H 3 K 27的tri- methylation是沉默的异染色质的主要特征 • 3. H 3 K 9的di- methylation对于常染色质的基因表达是必需的 • 4. H 4 K 20的tri- methylation是癌症中的一个普遍现象 • 5. 有丝分裂期间，在动粒(centromere)附近的H 3 K 9的trimethylation负责保证染色体顺利完成分裂 • 6. 在活化基因的5’端和启动子区域，甲基化出现的模式为： – A. H 4 K 20的mono- methylation – B. H 3 K 4的di- or trimethylation – C. H 3 K 79的di- methylation

Histone Modification Status Correlates with Transcriptional Activity • Gene activation correlated with H 3 -K 9 acetylation • Gene silencing associated with H 3 -K 9 methylation

组蛋白密码 • Histone code: The histone code hypothesis predicts that the post-translational modifications of histones, alone or in combination, function to direct specific and distinct DNAtemplated programs.

六、国际人类表观基因组计划 • 1. The Human Genome Project: provides the blueprint for life, but the epigenome will tell us how this whole thing gets executed. • 2. Human epigenome project: DNA methylation – (1) 不同组织、细胞 – (2) 不同发育阶段 – (3) 正常细胞 vs. 癌症、疾病细胞