組蛋白乙?;?/h1>
1964年,文森特·奧爾弗里及其團隊首次報告了組蛋白乙?;?[1]。組蛋白乙?;且环N被廣泛研究的組蛋白后轉(zhuǎn)錄修飾(PTM),在調(diào)控染色質(zhì)基因轉(zhuǎn)錄中發(fā)揮著核心作用。
1. 什么是組蛋白乙?;?/h2>
組蛋白乙?;侵笇⒁阴;砑拥浇M蛋白蛋白質(zhì)的N-末端賴氨酸殘基上的過程 [1]。所添加的乙酰基的負電荷中和了賴氨酸的正電荷,導(dǎo)致組蛋白與DNA的相互作用減弱,從而使染色質(zhì)結(jié)構(gòu)更加松弛,有助于轉(zhuǎn)錄因子接近基因組序列,從而增加基因表達。
已經(jīng)檢測到各種組蛋白蛋白質(zhì)上的組蛋白乙酰化。具體而言,H3上的賴氨酸殘基K4、K9、K14、K18、K23、K27、K36和K56顯示出乙?;?,而H4則在K5、K8、K12、K16、K20和K91上顯示出乙?;4送?,H2A和H2B也經(jīng)歷賴氨酸乙酰化,在H2A上的K5和K9被修飾,在H2B上的K5、K12、K15、K16、K20和K120被乙?;?/p>
2. 參與組蛋白乙?;拿富虻鞍?/h2>
組蛋白乙?;且粋€動態(tài)可逆的過程,由組蛋白乙酰化調(diào)節(jié)因子(HAMs)協(xié)同調(diào)節(jié),包括“寫入者”(組蛋白乙酰轉(zhuǎn)移酶)、“閱讀器”和“擦除者”(組蛋白去乙?;福?,它們分別負責(zé)添加、識別和去除乙?;ATs和HDACs之間的這種動態(tài)相互作用調(diào)節(jié)了組蛋白乙?;钠胶猓_保了基因表達模式的精確控制。
2.1 組蛋白乙酰轉(zhuǎn)移酶(HATs)
HATs,也稱為“寫入者”,負責(zé)將乙?;?COCH3)從乙酰輔酶轉(zhuǎn)移到H3或H4的靶賴氨酸殘基的ε-氨基上 [2]。HATS還乙?;鞣N非組蛋白底物,因此它們通常被歸類為賴氨酸乙酰轉(zhuǎn)移酶(KATs)。
基于它們的細胞定位,HAT可分為兩大類:A型HATs位于細胞核,乙酰化核小體組蛋白和其他染色質(zhì)相關(guān)蛋白,而B型HATs位于細胞質(zhì),專門乙?;潞铣傻挠坞x組蛋白,對轉(zhuǎn)錄沒有直接影響。
組蛋白乙酰轉(zhuǎn)移酶家族 | 成員 | 定位 | 組蛋白亞基 | 功能 | ||
---|---|---|---|---|---|---|
Type A HATs | GNAT | KAT2A (GCN5) | Nucleus | H3K9, H3K14, H3K18, H2B | Transcription activation | |
KAT2B (PCAF) | Nucleus | H3K9, H3K14, H3K18, H2B | Transcription activation | |||
MYST | KAT5 (Tip60) | Nucleus | H4K5, H4K8, H4K12, H4K16 | Transcription activation, DNA repair | ||
KAT6A (MOZ/MYST3) | Nucleus | histone H2B, H3K14 and H4K5, H4K8, H4K12 and H4K16 in vitro and H3K9 in vivo [3] | Transcription activation | |||
KAT6B (MORF/MYST4) | Nucleus | particularly H3 and H4, and nucleosomal histones with a preference for H4 | Transcription activation | |||
KAT7 (HBO1/MYST2) | Nucleus | H3K14, H4K5, H4K8, H4K12 | Transcription, DNA replication | |||
KAT8 (MOF/MYST1) | Nucleus | specifically H4K16 | Chromatin boundaries, dosage compensation, DNA repair | |||
P300/CBP | KAT3B (P300) | Nucleus | all four histone subtypes: H2AK5, H2B (K5, K12, K15, K20), H3 (K14, K18, K27), and H4 (K8, K12) | Transcription activation | ||
KAT3A (CBP) | Nucleus | |||||
Others | Transcription co-activators | KAT4 ( TAF1/TBP) | Nucleus | H3 and H4, H3K14 | Transcription activation | |
KAT12 (TIFIIIC90) | Nucleus | H3K9, H3K14, H3K18 | Transcription activation | |||
Steroid receptor co-activators | ATAT1 | Nucleus | - | - | ||
KAT13A (SRC1) | Nucleus | H3, H4 | Transcription activation | |||
KAT13B (SCR3/AIB1/ ACTR) | Nucleus | |||||
KAT13C ( p160) | Nucleus | |||||
KAT13D (CLOCK) | Nucleus | |||||
Type B HATS | KAT1 (HAT1) | Cytoplasm | H3, H4, H2A | Histone deposition, DNA repair | ||
HAT4 (NAA60) | Cytoplasm | H4, H2A | - |
表格參考來源:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881052/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311713/
2.2 組蛋白去乙酰化酶(HDACs)
HDACs,也被稱為“擦除者”,是一種能夠從乙?;慕M蛋白中去除乙酰基的酶。組蛋白去乙?;ㄟ^暴露賴氨酸殘基的正電荷,使DNA與組蛋白尾部之間發(fā)生相互作用,從而減少了DNA的可及性,導(dǎo)致染色質(zhì)緊縮和更加致密的染色質(zhì)結(jié)構(gòu),有效地抑制了基因表達。
HDACs在各種生理過程中至關(guān)重要,包括發(fā)育和細胞內(nèi)穩(wěn)態(tài),同時也參與了神經(jīng)退行性疾病、遺傳疾病和癌癥等病理條件的發(fā)生。
在人體中,根據(jù)它們與酵母的序列同源性,HDAC酶分為四個類別 [4]。I類HDACs包括HDAC1-3和HDAC8。II類HDACs包括HDAC4-7、HDAC9和HDAC10 [5-7]。III類HDACs,也被稱為sirtuins,包括SIRT1-7 [8,9],這些酶在活性時需要NAD+輔酶。IV類HDAC只有一種酶HDAC11 [10]。I、II和IV類HDACs是Zn2+依賴的酰胺水解酶。
組蛋白去乙?;讣易?/th> | 分類 | 亞族 | 成員 | 細胞定位 | 組蛋白亞基 | 生物學(xué)功能 |
---|---|---|---|---|---|---|
Classical (Zn2+-dependent) | Class I | HDAC1 | Nucleus | all four core histones [11] | Mediates deacetylation of lysine on the N-terminal part of the core histones and plays and important role in transcriptional regulation, cell cycle progression and development event | |
HDAC2 | Nucleus | all four core histones [11] | ||||
HDAC3 | Nucleus | H4K5 H4K12 H2AK5 | ||||
HDAC8 | Nucleus | preferentially deacetylates histones H3 and H4 [12] | ||||
Class II | Class IIa | HDAC4 | Nucleus | all four core histones [11] | ||
HDAC5 | Nucleus | all four core histones [11] | ||||
HDAC7 | Nucleus | |||||
HDAC9 | Nucleus | H3K9 H3K14 H3K18 [13] |
||||
Class IIb | HDAC6 | Cytoplasm | all four core histones [11] | |||
HDAC10 | Cytoplasm | H3K9 H3K14 H3K18 H3K27 [14] |
Involved in MSH2 deacetylation | |||
Class IV | HDAC11 | Nucleus | H3K9 H3K14 [15] H4K16 H4K5 H4K12 [16] |
Plays an important role in transcriptional regulation, cell cycle progression and developmental events | ||
NAD+-dependent | Class III | SIRT1 | Nucleus | H3K9 H3K14 H3K56 H4K16 H1K26 [11] |
Chromatin organization, DNA repair/genome stability, cancer | |
SIRT2 | Cytoplasm | H4K16 H3K56 [11] |
Chromatin condensation/mitosis, DNA repair, cancer | |||
SIRT3 | Mitochondria | H4K16 [11] | Chromatin silencing, DNA repair, cellular stress | |||
SIRT4 | Mitochondria | / | Regulates the cellular metabolic response to DNA damage | |||
SIRT5 | Mitochondria | / | Regulates the mitochondrial lysine succinylome and metabolic networks | |||
SIRT6 | Nucleus | H3K9 H3K56 [11] |
Telomeric chromatin/senescence, DNA repair/genome stability, energy metabolism | |||
SIRT7 | Nucleolus | H3K18 [11] | Mediates deacetylation of H3K18ac Mediates deacetylation of lysine residues on the N-terminal part of the core histones |
表格參考來源:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970420/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444376/
2.3 讀取蛋白
組蛋白乙?;x取蛋白特異地識別乙酰化的賴氨酸,并招募轉(zhuǎn)錄因子和其他調(diào)節(jié)蛋白與DNA結(jié)合,啟動轉(zhuǎn)錄,從而激活基因表達 [17,18]。它們通常是含有溴結(jié)構(gòu)域(BRD)的蛋白或者是乙酰化賴氨酸結(jié)合蛋白,比如BRD和額外末端結(jié)構(gòu)域(BET)家族,負責(zé)將乙?;盘柦忉尀榛虮磉_和染色質(zhì)重塑中的特定變化。
BRDs突出顯示為唯一能夠識別和結(jié)合乙酰化組蛋白賴氨酸殘基的蛋白群。它們廣泛分布在各種組織中,并根據(jù)序列或結(jié)構(gòu)相似性被分為八個家族,每個家族都顯示出多樣的活性,比如組蛋白修飾和染色質(zhì)重塑。
BRDs | Members |
---|---|
Class I | BAZ1A, BPTF, CECR2, GCN5L2, PCAF |
Class II | BRD2, BRD3, BRD4, BRDT |
Class III | BAZ1B, BRD8B, BRWD3, CREBBP, EP300, PHIP, WDR9 |
Class IV | ATAD2, ATAD2B, BRD1, BRD7, BRD9, BRPF1, BRPF3 |
Class V | BAZ2A, BAZ2B, SP100, SP110, SP140, SP140L, TRIM24, TRIM33, TRIM66 |
Class VI | MLL, TRIM28 |
Class VII | BRWD3, PHIP, TAF1, TAF1L, WDR9, ZMYND8, ZMYND11 |
Class VIII | ASH1L, PBRM1, SMARCA2, SMARCA4 |
表格參考來源:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686570/
3. 組蛋白乙酰化的機制
組蛋白酰轉(zhuǎn)移酶(HATs)?;M蛋白賴氨酸殘基,減少了組蛋白和DNA之間的靜電相互作用,導(dǎo)致染色質(zhì)結(jié)構(gòu)松弛。因此,DNA被暴露出來,有助于轉(zhuǎn)錄激活因子(TA)被招募到基因組序列上,激活基因表達。
相反,組蛋白去乙?;福℉DACs)可以與轉(zhuǎn)錄抑制因子(TR)復(fù)合物相互作用,去除這些乙酰修飾。這增強了DNA和組蛋白之間的靜電相互作用,導(dǎo)致緊湊的染色質(zhì),抑制轉(zhuǎn)錄。保持組蛋白乙?;腿ヒ阴;g的平衡對于正確的基因表達非常關(guān)鍵。
圖1. 組蛋白乙?;c去乙酰化機制
圖片參考來源:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820808/
4. 組蛋白乙?;墓δ?/h2>
大量研究數(shù)據(jù)表明,組蛋白乙酰化在細胞中廣泛存在,并參與各種細胞活動,包括核小體組裝的調(diào)節(jié)、染色質(zhì)的折疊和解構(gòu)、基因轉(zhuǎn)錄、DNA損傷修復(fù)、細胞周期和凋亡 [19]。
5. 與其他修飾的相互作用
組蛋白乙?;c其他組蛋白修飾之間存在復(fù)雜的相互作用,比如甲基化、磷酸化和泛素化。它們可以相互合作或拮抗,影響染色質(zhì)結(jié)構(gòu)和基因表達模式。
在釀酒酵母薩克羅米瑟斯小麥,Snf1激酶介導(dǎo)的H3S10ph促進了由Gcn5乙酰轉(zhuǎn)移酶介導(dǎo)的H3K14的乙酰化,在基因激活期間增強了組蛋白H3與14-3-3蛋白Bmh1和Bmh2的相互作用 [20]。在哺乳動物細胞中,H3K18ac和H3K23ac促使CARM1甲基轉(zhuǎn)移酶介導(dǎo)的H3R17甲基化,導(dǎo)致雌激素響應(yīng)基因的激活 [21]。
組蛋白修飾的相互作用也可以在去除特定修飾方面發(fā)揮作用。例如,在釀酒酵母中,與RNA聚合酶II結(jié)合的Set2甲基轉(zhuǎn)移酶甲基化H3K36,引導(dǎo)核小體在RNA聚合酶通過后由Rpd3S脫乙酰酶復(fù)合物去乙酰化H3和H4 [22]。
Wojcik等人證明,H2A的多個位點,包括K5、K9、K13和K15的乙酰化抑制了H2BK120的泛素化 [23]。
6. 發(fā)育和疾病
組蛋白乙?;瘏⑴c了許多生物學(xué)過程,包括發(fā)育、分化和對環(huán)境信號的響應(yīng)。組蛋白乙?;氖д{(diào)與各種疾病相關(guān),比如癌癥、神經(jīng)系統(tǒng)障礙和代謝性疾病,突顯了它在疾病發(fā)病機制中的重要性。
在癌細胞中觀察到異常的組蛋白乙?;J?,導(dǎo)致細胞不受控制地增長和腫瘤發(fā)生。HDAC抑制劑能夠恢復(fù)適當(dāng)?shù)囊阴;J?,被認為是潛在的治療某些癌癥的方法,提供了一種新的方式來靶向癌細胞而不傷害正常細胞。
在神經(jīng)退行性疾病中,比如阿爾茨海默病和帕金森病,組蛋白乙?;奈蓙y與與神經(jīng)細胞存活和功能相關(guān)的基因表達模式的變化有關(guān)。失調(diào)的組蛋白乙?;赡軐?dǎo)致神經(jīng)退行性病變和疾病進展。
此外,組蛋白乙?;€與代謝性疾病相關(guān),它可能影響與葡萄糖代謝和脂質(zhì)穩(wěn)態(tài)有關(guān)的基因的表達。對飲食和環(huán)境因素的反應(yīng)引發(fā)的表觀遺傳變化可能導(dǎo)致代謝失調(diào)和與肥胖相關(guān)的疾病。
總的來說,HATs、HDACs和BRDs形成了一個復(fù)雜的調(diào)節(jié)網(wǎng)絡(luò),控制組蛋白的乙?;癄顟B(tài),從而影響基因?qū)D(zhuǎn)錄的可及性。這種表觀遺傳機制在各種生物學(xué)過程中發(fā)揮著關(guān)鍵作用,包括發(fā)育、分化和對環(huán)境信號的響應(yīng)。這些酶的失調(diào)可能導(dǎo)致基因表達模式的異常,與多種疾病相關(guān),使它們成為治療干預(yù)和藥物開發(fā)的有希望的靶點。
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