染色质修饰及其作用机理

染色质的高级结构
核小体结构
染色质模板
核小体结构

2.8Å的核小体模型（左），X射线晶体衍射核小体结构（中）， 组蛋白核心八
聚体被DNA盘绕结构的图示（右）。
组蛋白尾部从核小体表面伸出。
Histone variants
组蛋白修饰
组蛋白尾巴的修饰位点

活化修饰：乙酰化，精氨酸甲基化，赖氨酸甲基化（H3K4，H3K36 ，H3K79 ）。
Nature Reviews Drug Discovery 2006, 5, 769-784
HDACs
The class I HDACs (1, 2, r3 and 8) are homologous to the yeast RPD3 protein, can generally be detected in the nucleus and show ubiquitous expression in various human cell lines and tissues. Class II HDACs (4, 5, 6, 7, 9 and 10) share homologies with the yeast Hda1 protein and can shuttle between the nucleus and the cytoplasm.


Epigenetic differences：monozygotic twins

(Upper) Quantification of global 5mC DNA content (Left), histone H4 acetylation (Center), and histone H3 acetylation (Right) by HPLC and high-performance capillary electrophoresis. (Lower) Comparison of epigenetic values between the siblings of each 3- and 50-year-old twin pair. Fraga MF, Proc Natl Acad Sci U S A. 2005, 26; 102(30): 10604–10609
染色质修饰及其作用机理
DNA Packing
1. 如何将10,000公里长的蚕 丝(半径~10-5米)装入一个篮球 中。 2. 蚕丝的体积：3.14*10-3m3 3. 折叠、缠绕…

DNA—2nm， 核小体串珠—11nm， 染色质纤维—30nm， 染色质高级环状结构—300-700nm， 间期染色体—1400-1500nm。
蛋白质乙酰化调控基因转录
(a)
Transcription factors (TF) can be acetylated (indicated by a flag) by histone acetyltransferase(s) (HAT), and this acetylation increases the binding of TF (such as p53, see text) to a DNA sequence. The activation domain of TF can recruit a HAT complex to the promoter.
Current Opinion in Cell Biology 2000, 12:326–333
(d)
(e)
(f)
组蛋白修饰与DNA损伤修复
r
DNA损伤修复： A. Homologous recombination (HR) B. Nonhomologous end-joining (NHEJ)
A. 完整的DNA序列；
B. 双链断裂； C. NHEJ因子: (D) 修复因子与(E)染色 质重塑因子；红色：磷酸化，蓝色：乙酰 化，黄色：去乙酰化； F. 染色质重塑的构型，(G) 增大NHEJ 局部浓度；
H. 直至修复
Fernandez-Capetillo O , Nussenzweig A PNAS 2004;101:1427-1428
人类IFN-β基因的激活
Cell. 2002 Nov 1;111(3):381-92.
(A) (B) (C) (E) The DNA code contains all the information for the assembly of the enhanceosome in response to virus infection. DNA code information processing. The enhanceosome recruits the GCN5 histone acetyltransferase. (C and D) GCN5 acetylates initially H4K8 and H3K9 (C). An unknown kinase recruited by the enhanceosome phosphorylates H3 Ser 10, a prerequisite for H3K14 acetylation by GCN5 (D). The histone code is printed. Translation of the histone code. The bromodomain containing transcription complexes SWI/SNF and TFIID are recruited to the promoter via bivalent interactions between the enhanceosome and specifically acetylated histone N termini.
染色质的高级结构
DNA Packing
Organization of DNA Within a Cell
2 meters of DNA is packed into a 10 mm diameter cell
from Lodish et al., Molecular Cell Biology, 6th ed. Fig 6-1
Eighteen HDACs have been identified in humans, and they are subdivided into four classes based on their homology to yeast HDACs, their subcellular localization and their enzymatic activities.
内容提要
一、组蛋白的乙酰化 二、组蛋白的甲基化 三、组蛋白的磷酸化 四、组蛋白的泛素化 五、组蛋白的SUMO化 六、组蛋白密码
一、组蛋白的乙酰化
一、组蛋白的乙酰化
已知组蛋白乙酰化位点
一、组蛋白的乙酰化
组蛋白乙酰基转移酶-HATs
Gcn5/PCAF & p300/CBP
(b)
(c)
The HAT complex then acetylates the relevant residues of the histone tails to ‘open’ up the chromatin.
The ‘open’ chromatin allows the basal transcription machinery (BTM) to bind and initiate transcription. Later, HATs, co-activators or other factors in the HAT complex are acetylated by a regulatory HAT. After acetylation, the HAT complex loses its affinity for the TF and thus dissociates. Eventually, the decrease level of bound HAT complex ‘closes’ the chromatin and decreases transcription. The flag symbol indicates acetylation.

抑制修饰：赖氨酸甲基化（H3K9，H3K27，H4K20）。
源自文库
组蛋白修饰与修饰酶（1）
组蛋白修饰与修饰酶（2）
主要的功能基团
Acetyl Methyl
Phosphoryl
Ubiquitin
Epigenetic differences：monozygotic twins
Differential DNA methylation between MZ twins using AIMS. (A Left) Example of an AIMS analysis in 3- and 50-year-old twin pairs. Differential bands corresponding to DNA methylation are indicated with arrows. (A Right) Number of differential bands obtained by AIMS in 3- and 50-year-old twin pairs. (B) Bisulfite genomic sequencing of 12 clones of the repetitive DNA sequence Alu-SP obtained by AIMS in 3- and 50-year-old twin pairs. Schematic representations of the methylation status of each CpG dinucleotide. Black and white dots indicate methylated and unmethylated CpGs, respectively.
Bromodomain
1. An acetyl-lysine binding domain 2. HATs修饰底物之 后可能与底物上的乙 酰化赖氨酸结合
HATs: MYST(MOZ-Ybf2/Sas3-Sas2-TIP60)
HAT识别底物的分子机制
Nucleic Acids Res, 2004, 3: 959-976
HDACs
r Histone deacetylases (HDACs) catalyse the removal of acetyl groups from lysine residues in histone amino termini, leading to chromatin condensation and transcriptional repression.
Epigenetic differences：monozygotic twins
Mapping chromosomal regions with differential DNA methylation in MZ twins by using comparative genomic hybridization for methylated DNA. Examples of the hybridization of chromosomes 1, 3, 12, and 17 are displayed. The 50-year-old twin pair shows abundant changes in the pattern of DNA methylation observed by the presence of green and red signals that indicate hypermethylation and hypomethylation events, whereas the 3-year-old twins have a very similar distribution of DNA methylation indicated by the presence of the yellow color obtained by equal amounts of the green and red dyes. Significant DNA methylation changes are indicated as thick red and green blocks in the ideograms.