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通讯作者:

郭帆(1986-),男,湖北宜昌人,研究员,主要从事表观遗传及其发育和疾病关系的研究。E-mail:guofan@ioz.ac.cn

中图分类号:Q34

文献标识码:A

文章编号:2096-8965(2022)04-0002-13

DOI:10.12287/j.issn.2096-8965.20220401

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目录contents

    摘要

    哺乳动物卵母细胞发育过程中呈现出独特的表观遗传修饰模式。包括DNA甲基化和组蛋白修饰等在内的表观遗传修饰的建立,是一个复杂但高度有序的过程,对哺乳动物卵母细胞成熟和早期胚胎发育至关重要。因此,探究并揭示卵母细胞表观遗传特征建立的机制,对深入理解哺乳动物生殖发育机理和相关疾病的发生发展具有重要意义。本文以小鼠和人类为典型代表,阐述了哺乳动物卵母细胞发育过程中DNA甲基化以及组蛋白甲基化、乙酰化、泛素化、磷酸化和乳酸化的分布模式和动态变化特征,总结并探讨了这些表观遗传修饰之间潜在的关联及影响其发挥生物学功能的多种调控因素。

    Abstract

    The unique patterns of epigenetic modifications appear in mammalian oocyte development. Establishment of these modifications, including DNA methylation and histone modifications, is a complicated but highly ordered process, which is crucial in terms of oocyte maturation and early embryo development in mammals. Therefore, dissecting the mechanisms of epigenetic establishment in oocytes is of great significance to look insight into the principles of reproduction and pathogenesis of related diseases. In this review, we delineate the distribution patterns and dynamic landscapes of DNA methylation as well as histone methylation, acetylation, ubiquitination, phosphorylation and lactylation in mammalian oocyte development represented by mice and humans. Meanwhile, we present a summary and discussion in the matter of the potential relevance among these epigenetic modifications, which are regulated by multiple factors related to biological functions.

  • 1 概述

  • 1.1 表观遗传修饰

  • 表观遗传修饰是指细胞核内基因组在不改变其自身序列的情况下,发生可遗传的、可逆的功能性变异。DNA甲基化和组蛋白修饰(甲基化、乙酰化、泛素化、磷酸化、乳酸化等) 作为表观遗传修饰的重要部分被广泛研究[1] (见图1)。结果表明,基因表达不仅受顺式调控元件和转录因子的共同调节,同时也受DNA甲基化以及组蛋白修饰的协同调控[2-4]

  • 图1 DNA和组蛋白的共价修饰

  • 1.1.1 DNA甲基化

  • DNA 甲基化一般是指在 DNA 甲基转移酶 (DNA Methyltransferases,DNMTs) 的催化下将 S-腺苷甲硫氨酸 (S-Adenosyl Methionine,SAM) 的一个甲基连接到胞嘧啶残基的5号碳原子上的共价修饰[56]。DNA 的胞嘧啶残基被可逆地加上甲基基团后,可以招募 DNA 结合蛋白或者直接阻断转录因子与 DNA 的结合位点从而发挥转录调控作用[7]。在脊椎动物中,胞嘧啶的甲基化主要发生在CpG二核苷酸序列上,且有大约 70%~80%的 CpG 位点在哺乳动物体细胞中被甲基化[8]。当DNA甲基化发生在异染色质、基因启动子、重复元件 (Repetitive Elements,REs) 和转座元件上时,其被认为是一种抑制性标记;相反,基因本体 (Gene Body) 上的甲基化与较高的转录水平有关[9]

  • 1.1.2 组蛋白修饰

  • 组蛋白 N-末端具有突出的尾巴,可以获得甲基化、泛素化等大量的翻译后修饰 (Post-Translational Modifications, PTMs) [10]。组蛋白 PTMs 通常分布于特定的基因组区域且参与调控相关基因的活性状态。例如,在活性启动子和转录起始位点 (Transcription Start Sites,TSSs) 上的组蛋白 H3 亚基 4 号赖氨酸三甲基化 (Histone H3K4 trimethylation, H3K4me3) 与基因激活有关,而 H3K36me3通常与活跃转录的基因本体相关[1112]。此外,在特定基因组中存在H3K4me3和H3K27me3的共定位,这种二价修饰使发育相关的调节基因处于 “蓄势待发”的瞬时激活状态,以便快速响应外界的分化信号[13]

  • 1.2 哺乳动物卵母细胞的发育

  • 小鼠 6.25 天胚胎 (E6.25) 中开始出现 B 淋巴细胞诱导的成熟蛋白 1 (B-lymphocyte-induced maturation protein-1,BLIMP-1) 表达的生殖细胞前体;E7.25 时,这些细胞发育为原始生殖细胞 (Primordial Germ Cells,PGCs) 且聚集在近端外胚层 (Proximal Epiblast) 中;E11.5时,PGCs沿着后肠内胚层 (Hindgut Endoderm) 迁移至性腺原基定植并形成胚胎性腺。随着有丝分裂的不断进行,直到 E13.5 时,PGCs 数量达到 25 000 个左右[14-16]。在此期间,胞质不完全分裂的PGCs形成生殖细胞簇,并与其外包围的体细胞共同构成生殖细胞合胞体 (Germ-Cell Syncytium)。与此同时,部分由 PGCs 特化形成的卵原细胞 (Oogonia) 进入第一次减数分裂的前期,随后在终变期停滞[17]。这些未发育卵母细胞 (Non-Growing Oocyte,NGOs) 与其外包裹的单层鳞状前颗粒细胞共同构成原始卵泡 (Primordial Follicles)。雌性哺乳动物一生中所有可受精的卵子全部来源于这些原始卵泡,但在整个生殖寿命内,只有一部分原始卵泡可以被激活并提供发育成熟的卵母细胞[18]。当原始卵泡被选择性地激活后,卵泡进入生长阶段,此时卵母细胞被称为发育中卵母细胞 (Growing Oocytes,GOs)。GOs 的核糖体生物合成过程高度活跃,并可形成完整核仁,该结构被称为生发泡 (Germinal Vesicle,GV)。此时,卵母细胞进入减数分裂成熟的准备阶段。当卵泡中形成充满液体的腔体结构时,卵母细胞生长至最大尺寸并具有恢复减数分裂的能力,其被称为完全生长的卵母细胞 (Fully Grown Oocytes, FGOs)[19]。在促性腺激素的作用下,FGOs发生核膜去组装和生发泡破裂 (Germinal Vesicle Breakdown, GVBD),从而恢复第一次减数分裂并排出第一极体,直到第二次减数分裂中期再次停滞[20]

  • 2 哺乳动物卵母细胞中的DNA甲基化

  • 2.1 DNA甲基化模式

  • 相比于体细胞和精子,哺乳动物卵母细胞具有独特的 DNA 甲基化谱。在小鼠中,受精后胚胎会发生两次大规模去甲基化,为出生后卵母细胞的 DNA 甲基化重编程提供必要前提。第一轮发生在受精卵至植入前囊胚中,内细胞团 (Inner Cell Mass,ICM) 仍保留约40%的甲基化水平。第二轮去甲基化发生在 E6.25 时期 PGCs 起始增殖和迁移的过程中,此次 DNA 甲基化几乎被完全擦除,至 E13.5时期PGCs全基因组范围的DNA甲基化水平降至5%左右[21]。与之类似,在受精后10-11周的人类早期胚胎中,PGCs 内的甲基化水平也下降至最低点,约为 6%~7%[22]。直到出生后,DNA 甲基化在 GOs中的水平显著提升并在FGOs中基本建立完成。

  • 利用全基因组亚硫酸氢盐测序 (Whole Genome Bisulfite Sequencing,WGBS) 技术对小鼠卵母细胞生长过程中 DNA 甲基化的分布特征进行分析,揭示了小鼠和人类卵母细胞中 DNA 甲基化的双峰模式,即大多数基因组聚集为大规模的高甲基化或低甲基化区域[23-25]。另外,相关研究发现,小鼠 GV 期卵母细胞 (Germinal Vesicle Oocytes,GVOs) 中还普遍存在非CpG (non-CpG,CpH) 位点的胞嘧啶甲基化,其甲基化水平是 NGOs 的 4 倍,说明 CpH 甲基化也是在卵母细胞生长过程中积累起来的[9]。在卵母细胞生长阶段,CpH甲基化主要聚集在全基因组高度甲基化的CpG位点附近,且在基因本体中明显富集[9]。有研究发现,卵母细胞中 DNMT3A 或 DNMT3L的缺失同样会导致CpH位点甲基化水平的降低,表明 CpH 甲基化的建立也依赖于 DNMT3ADNMT3L复合体。这在一定程度上可以解释CpH甲基化和CpG甲基化在卵母细胞成熟过程中表现出的强正相关性和相似的动态变化[9]

  • DNA 甲基化在 PGCs 时期处于极低水平,但其基因表达网络基本维持稳定,意味着早期生殖细胞中的染色质可及性对于基因转录调控可能起了更为关键的作用。近年来,单细胞多组学技术的发展为 DNA 甲基化联合转录活性和染色质可及性动态变化的研究提供了良好的技术平台[2627]。在小鼠中,发生从头甲基化 (De Novo Methylation) 的基因本体与活跃的转录高度相关,这些基因往往会在卵母细胞起始发育前打开启动子区域[26]。卵母细胞发育的拟时间序列分析证明,在 NGOs向 GOs转变的过程中染色质可及性显著升高,而且一些表观遗传修饰和相关转录因子在卵母细胞成熟过程中发生阶段特异性富集[26]。此外,卵母细胞中的DNA甲基化与组蛋白修饰的分布也具有一定的关联。有研究表明,部分甲基化结构域 (Partially Methylated Domains,PMDs) 与卵母细胞中宽域分布的非经典 H3K4me3 (noncanonical H3K4me3, ncH3K4me3) 具有相关性。异常的 H3K4甲基化会破坏母源印迹基因的从头甲基化,而赖氨酸去甲基化酶 1A/1B(Lysine Demethylase1A/1B,KDM1A/1B) 可消除这种不利影响,进而帮助印迹CpG位点重新建立正确的DNA甲基化[28]

  • 相比小鼠,人类卵母细胞样本稀缺难以获得,传统的基于大量细胞的 DNA 甲基化分析方法不适用于珍贵的人类卵母细胞样品。2021年,Yan等[27] 开发了融合单细胞转录组、DNA 甲基组以及染色质开放性的多组学测序技术 (single-cell Chromatin Accessibility, RNA Barcoding, and DNA Methyla⁃ tion Sequencing,scChaRM-seq),从而在有限的样本中获得更丰富全面的单细胞表观遗传信息。研究发现,人类卵母细胞生长过程中的诸多表观遗传特征与小鼠类似:DNA 甲基化在全基因组水平上的升高与染色质可及性相关,且早期GOs中发生从头甲基化的相关基因的启动子区域保持开放状态;而随着 DNA 甲基化组的建立,全基因组的染色质可及性都有所降低[27]。值得注意的是,在人类卵母细胞中,活跃转录的基因间区以及随机基因间区也具有较高的DNA甲基化水平[27]。而且在卵母细胞生长过程中,这两个区域的染色质可及性是大体相同的,暗示这些开放的染色质可能有助于 DNMTs 的招募[27]。对不同基因组元件的进一步分析表明,人类卵母细胞中的 CpG岛 (CpG Islands,CGIs) 和生殖系差异甲基化区域 (germline Differentially Methyl⁃ ated Regions,gDMRs) 是最具可变性的元件[27]。与小鼠不同的是,Alu元件在早期发育的人类卵母细胞中保持较低的DNA甲基化水平和较高的染色质开放程度,这些Alu元件往往位于重要功能基因附近,其关联基因在小鼠和人类间并不保守[27]。这些工作为剖析哺乳动物卵母细胞生长过程中复杂的、高度协调的DNA甲基化建立机制铺平了道路。

  • 2.2 DNA甲基化建立过程中的调控因子

  • DNMT3s家族成员在卵母细胞DNA从头甲基化过程中发挥至关重要的作用。在小鼠中,DNMT3A, DNMT3B和DNMT3L的水平随卵母细胞的发育产生波动:在重新建立 DNA 甲基化的 GVOs 中达到峰值,在 MⅡ期卵母细胞中有所下降[29]。DNMT3A 及其辅因子DNMT3L主要负责具有转录活性的基因本体甲基化,在PGCs中敲除Dnmt3a虽不影响雌性个体出生和卵母细胞发育,但该缺陷型个体由于母源印迹基因的丢失而无法产生存活后代,这与Dnmt3l 缺失突变导致的表型是一致的[3031]。相较之下, DNMT3B对母源印迹基因的建立是非必要的[32]。尽管DNMT3L在小鼠卵母细胞从头甲基化过程中发挥招募 DNMT3A 的关键作用,但在人类卵母细胞中并未检测到DNMT3L的表达,且DNMT3B的表达量为 DNMT3A 的 10 倍,这表明 DNMT3B 可能是从头甲基化建立的驱动因素[24]。此外,长末端重复反转录转座子 (Long Terminal Repeat-Retrotransposons, LTR-RTs) 在基因组中的插入具有物种特异性,且由其引发的转录本单元 (LTR-Initiated Transcrip⁃ tion Units,LITs) 在发育卵母细胞中具有很高的丰度。这些 LITs 被证明与物种特异性的 DNA 甲基化结构域相关[2133]

  • 在卵母细胞生长过程中还存在其他参与调控 DNA 甲基化重建的关键因子。具有植物同源结构域 (Plant Homeodomain,PHD) 和环指结构域的泛素样蛋白 1 (Ubiquitin Like with PHD and Ring Finger Domains 1,UHRF1) 可发挥泛素连接酶作用并识别半甲基化的 DNA,从而将活性 DNMT1 招募到这些位点[34]。在敲除 Uhrf1 的卵母细胞中, DNMT1 核定位信号的丢失导致全基因组 DNA 甲基化水平下降约 8%[35]。此外,相关研究表明发育多能相关因子 3 (Developmental Pluripotency-Associated 3,DPPA3) 可调节 UHRF1 在卵母细胞中的定位。敲除 Dppa3 会导致细胞质中的 UHRF1 转移至细胞核内,从而促使 DNA 甲基化水平的异常增加[36]。常染色质组蛋白赖氨酸甲基转移酶 2/1 (Euchromatic Histone Lysine Methyltransferase2/1, EHMT2/EHMT1) 复合体主要负责催化H3K9me2的形成[37]。与体细胞类似,EHMT2在胚胎发生过程中通过建立 H3K9me2 启动基因组的异染色质化,并为DNA甲基化招募新生DNMT3s [38]。EHMT2在早期卵母细胞阶段开始表达,其表达水平和 H3K9me2 的丰度都随着卵母细胞的生长而增加[39]。Spalt样转录因子4 (Spalt-like Transcription Factor 4,SALL4) 也参与 DNA 甲基化的调控。SALL4 从初级卵泡阶段开始表达并定位于卵母细胞核中,卵母细胞发育至 MⅡ期后,SALL4 的定位转移到细胞质中[40]Sall4 敲除的卵母细胞无法发育成熟且细胞核中的 DNMT3A 信号丢失,进而导致 5-甲基胞嘧啶 (5-methylcytosine,5-mC) 水平大幅下降[40]

  • 综上,在哺乳动物中,存在多种调控因子协同参与卵母细胞 DNA 甲基化的建立 (见表1),探究其作用机制和发生机理对深入理解影响卵母细胞发育成熟的表观遗传特征具有重要意义。

  • 表1 哺乳动物卵母细胞中DNA甲基化的相关调控因子[41]

  • 3 哺乳动物卵母细胞中的组蛋白修饰

  • 组蛋白是染色质的另一基本组成部分,其表观修饰也在调控哺乳动物卵母细胞发育过程中扮演极其重要的角色。值得注意的是,组蛋白修饰不仅存在多样的表现形式,还与 DNA 甲基化协同影响卵母细胞成熟甚至早期胚胎发育中时空特异性基因表达模式的建立和维持。

  • 3.1 组蛋白甲基化

  • 3.1.1 H3K4me3

  • H3K4me3是研究较为深入的一种组蛋白修饰,其作为活性染色质的标志在发育相关基因的启动子上大量富集且参与转录正向调控[42]。H3K4me3的形成需要组蛋白甲基化转移酶 (Histone Methyltrans-ferases,HMTs) 的催化。在哺乳动物中,存在两类 HMTs参与上述过程,分别是含有 SET 结构域的1 A/1B (SET Domain-containing1A/1B, SETD1A/ 1B) 和混合谱系白血病因子 1-4 (Mixed Linage Leukemia1-4,MLL1-4) [43]

  • 从机制方面来看,CxxC指蛋白1 (CxxC-Finger Protein 1,CFP1) 可以识别 CGIs 上的非甲基化位点,从而招募 SETD1 复合物结合到指定的基因组区域上[4445]。研究者在小鼠原始卵泡阶段的卵母细胞中特异性敲除 Cfp1 基因,发现母源 CFP1 蛋白表达缺失会导致卵母细胞和受精卵中 H3K4me3 水平的降低,这造成卵母细胞成熟相关基因的转录活性严重不足及受精后胚胎在2细胞时期发育停滞等一系列负面影响[46]。有趣的是,同样作为催化因子的 MLL2虽然也可以介导H3K4me3靶向富含CpG的序列,但这些区域定位于启动子之外。卵母细胞中敲除 Mll2 基因,几乎并不影响转录相关 H3K4me3 的维持及发育基因的表达[47]

  • H3K4me3 在卵母细胞发生发育过程中存在不同的分布模式。在卵母细胞走向成熟的过程中, H3K4me3 仅在启动子区域高度富集;随着卵母细胞完成发育,基因转录活性被逐渐封闭,ncH3K4 me3 在启动子外的区域广泛分布 (见图2)。受精后,不同于父源 ncH3K4me3 的耗竭,母源 ncH3K4me3可经合子基因组继承并在晚期2细胞胚胎中才被KDM5A/5B擦除,进而引发大规模合子基因组激活 (Zygote Genome Activation,ZGA) 并重新建立经典模式的H3K4me3[48-50]

  • 图2 小鼠卵母细胞生长过程中的表观遗传修饰动态变化

  • 3.1.2 H3K27me3

  • 尽管在功能上,H3K27me3作为转录抑制性的染色质标志物与 H3K4me3 发挥截然相反的作用,但二者在卵母细胞成熟和早期胚胎发育过程中的建立和重编程模式具有很高的相似度。在哺乳动物中,含有多梳基团 (Polycomb Group Protein,PcG) 的多梳抑制复合物 2 (Polycomb Repressive Complex 2,PRC2) 可以在亚基组分 Jumonji 和 AT-富集互作域蛋白 2 (Jumonji and AT-rich Interaction Domain Containing2,JARID2) 的作用下优先识别富含 CG 的序列,进而指导H3K27me3靶向发育基因的启动子区域[51]。此外,H3K27me3也在 CGIs和启动子之外的序列上具有富集程度低却分布广泛的特点。虽然有研究指出染色质上的DNA甲基化与H3K27me3 修饰之间可能存在反相关性,但二者在一些低 CG 区域上仍有重叠[52] (见图2)。与 H3K4me3 类似,经典H3K27me3模式跟随卵母细胞成熟和受精后早期胚胎发育进程经历了建立、擦除和重编程过程; 而非经典 H3K27me3 (noncanonical H3K27me3, ncH3K27me3) 可以等位基因特异性的方式由成熟卵母细胞向受精卵传递,并可维持到胚胎植入前[53]

  • 既然经典模式的 H3K27me3 和 H3K4me3 均在发育基因启动子上存在明显的积累峰,那么探讨二者如何形成“二价”结构并发挥相关作用,对于深入理解多种组蛋白修饰互作在表观遗传调控中的影响是具有积极意义的。H3K4me3和H3K27me3之间微妙的关系影响了染色质结构,导致下游基因产生平衡、激活和抑制三种状态:在谱系决定期间,依赖 H3K4me3 激活的谱系控制基因可被 H3K27me3抑制以维持细胞干性;一旦接收到发育信号,这种平衡状态被打破,基因转录进入开启或关闭的状态,进而启动不可逆且自发的分化程序[54]。这种启动子二价结构虽然已在小鼠 PGCs、胚胎干细胞 (Embryo Stem Cells,ESCs) 和精子中被发现[55-57],但在植入前早期胚胎中分布相对较少且不稳定[49]。此外,在卵母细胞中,不论是在启动子还是在 PMDs上均未找到二价结构存在的有力证据[53]

  • 3.1.3 H3K36me2/3

  • 在分布模式上,H3K36me3与成熟卵母细胞基因本体上的 DNA 甲基化密切偶联,而与 PMDs 中 H3K4me3 和 H3K27me3 的累积反相关;在功能上, H3K36me3可以正向调控卵母细胞发育相关基因的表达[58] (见图2)。此外,H3K36me2在卵母细胞基因间区和基因结构域等一些中度 CG 甲基化区域 (Moderately Methylated Regions,MMRs) 上特异性富集[59]

  • 在机制上,小鼠卵母细胞中的从头 DNA 甲基化依赖于甲基转移酶 SETD2 介导的 H3K36me3 建立,并且 H3K36me2 的累积也需要 SETD2 的指导。敲除 Setd2后,卵母细胞内 DNA 甲基化建立失败并引发部分 H3K27me3 异位侵占其原有位点。母源 Setd2 的缺失还可导致 1 细胞胚胎发育阻滞和 ZGA 失败等一系列严重的后果[58]。此外,其他研究结果表明,卵母细胞内同时丢失 H3K36me2 和 H3K36me3 会造成与敲除 Dnmt3a 相当水平的 DNA 低甲基化[59]。总之,H3K36me2 和 H3K36me3 共同组成了支持哺乳动物卵母细胞从头 DNA 甲基化景观建立的平台。

  • 3.2 组蛋白乙酰化

  • 在核心组蛋白中,含有碱性侧链的氨基酸占比较高,其在生理条件下携带正电荷,这使得组蛋白在静电相互作用力的影响下,被吸引到携带负电荷的 DNA 上并形成核小体。然而,赖氨酸乙酰化 (Lysine acetylation,Kac) 可以减少组蛋白表面的正电荷,从而削弱组蛋白与 DNA 之间的静电亲和力,进而导致开放染色质结构的形成和基因转录活性的增强[60-62]。因此,与 H3K4me3 类似,Kac 可作为开放染色质的标志物。在哺乳动物卵母细胞中,组蛋白乙酰化通常发生在H3和H4亚基上的赖氨酸残基上,且乙酰化修饰谱随卵母细胞减数分裂成熟发生动态变化。

  • 在小鼠早期发育的卵母细胞中,H3K9ac 和H4K12ac 等多种组蛋白乙酰化修饰不断积累并于 GV 期达到峰值;之后,这些修饰在 GVBD 期卵母细胞内的水平出现明显下降,直至 M Ⅱ 期除 H4K8ac 外几乎被完全擦除[396364]。同样,在人 GVOs 中也可观测到 H4K5ac、H4K8ac、H4K12ac 和H4K16ac强烈的富集信号,但随着减数分裂进程的发展,在MⅠ和MⅡ期卵母细胞中仍存在不同程度的乙酰化残留[65]。此外,Wang等[66] 通过比较人类卵母细胞和植入前早期胚胎中 H3K56ac、H3K64ac 和 H3K122ac 的表达情况发现,H3K64ac 在各个阶段都具有较高水平,而 H3K122ac 富集程度很低。值得关注的是,H3K56ac在 2细胞胚胎中的相对表达水平最高,且染色质免疫共沉淀测序 (Chromatin Immunoprecipitation and Sequencing, ChIP-seq) 数据显示,H3K56ac的分布与长散在核元件 (Long Interspersed Elements,LINEs) 和LTRRTs高度相关,表明 H3K56ac可能参与受精后早期胚胎基因表达调控,并对8细胞胚胎阶段的ZGA事件具有潜在影响[66]

  • 从总体上看,组蛋白乙酰化可帮助形成染色质松散结构并促进基因表达,为卵母细胞早期发育的物质积累提供了必要前提;相应地,组蛋白去乙酰化对染色质凝集和卵母细胞减数分裂的顺利进行至关重要。组蛋白乙酰化水平的动态变化需要受到组蛋白乙酰转移酶 (Histone Acetylation Transferases, HATs)和组蛋白去乙酰化酶(Histone Deacetylases, HDACs)的共同调控[67]

  • HATs共包括 GNAT、MYST 和 p300/CBP 3个亚家族。作为MYST家族成员之一,赖氨酸乙酰转移酶 (Lysine Acetylation Transferase8,KAT8) 高度保守,且为目前首个被证明在小鼠卵泡发育过程中发挥重要调控作用的 HATs。研究人员发现,Kat8 及其主要组蛋白靶标 H4K16ac在小鼠 GVOs中高表达;而 Kat8 的缺失会导致活性氧自由基 (Reactive Oxygen Species,ROS) 水平提升,进而引发卵母细胞早期凋亡和卵泡发育缺陷[68]。另外,有证据表明在小鼠胚胎干细胞 (mouse ESCs,mESCs) 中,组蛋白变体 H3.3 特异性磷酸化能够刺激 p300 发挥组蛋白乙酰转移酶活性,从而促进增强子处H3K27ac 的累积[69]

  • 在哺乳动物中鉴定出的 18 种 HDACs 可分为 4 类,Ⅰ类包括具有核定位特性的 HDAC1、2、3 和 8;Ⅱ类包括可自由出入细胞核的两个亚类,分别为 Ⅱ a 类的 HDAC4、 5、 7 和 9,以及 Ⅱ b 类的 HDAC6 和 10; Ⅲ 类由被称为 “ 长寿蛋白 ” 的 Sirtuin1-7 (SIRT1-7) 组成,Ⅳ类仅含有 HDAC11 且与Ⅰ类和Ⅱ类具有同源性[70]

  • HDAC1 和 HDAC2 的氨基酸序列同源性高达 83%,二者尽管在组蛋白乙酰化修饰等事件中存在一定的代偿作用,但在卵母细胞和植入前胚胎发育过程中展现出差异化表达谱。HDAC1 主要参与植入前胚胎中的细胞周期调节和 ZGA 等;而 HDAC2 不仅可以介导 H4K16 的去乙酰化从而调控卵母细胞成熟过程中的染色体分离,还通过与 DNMT3A2 的互作负责 DNA 从头甲基化和印迹基因的建立[7172]。此外,Hdac1Hdac2双缺失突变的卵母细胞在GVBD前即出现发育停滞的现象,尽管组蛋白乙酰化仍维持较高水平,但 H3K4甲基化建立和转录活性受到严重影响[73]。最新研究结果发现,在卵母细胞减数分裂成熟和母源向合子转换 (Maternalto-Zygotic Transition,MZT) 期间,H3K27ac 经历了由 p300/CBP 和 HDACs 介导的重编程。具体而言,H3K27ac在GVOs中建立起非经典的宽域模式,而到 MⅡ期仅在有限的区域中保留。在 MZT 过程中,p300/CBP 帮助重建受精卵中 H3K27ac 的非经典模式,以诱导染色质在特定增强子处保持开放,从而为转录激活创造条件;相反,在早期2细胞胚胎中,HDACs 将非经典 H3K27ac 结构域迅速恢复为经典模式,并通过防止发育基因的过早表达来保护 ZGA 事件。因此,p300/CBP 和 HDACs 在小鼠 MZT过程中的协调活性对于卵母细胞成熟时的ZGA 和植入前早期胚胎发育至关重要[74]

  • Sirtuins 以依赖于烟酰胺腺嘌呤二核苷酸 (Nicotinamide Adenine Dinucleotide,NAD) 氧化形式的途径发挥蛋白质去乙酰化作用[75]。已有研究表明,SIRT7是卵母细胞第一次减数分裂前期中同源染色体联会的重要调控因子,而敲除 Sirt7 将导致 H3K18ac水平异常增高和染色体联会受损[76]。多项独立研究表明,HDACs 也可靶向作用于非组蛋白乙酰化位点。其中,HDAC3、HDAC6 和 SIRT1 是小鼠卵母细胞内重要的 α-微管蛋白去乙酰化酶,对纺锤体正确组装和染色体有序运动至关重要[77-79]; HDAC8 靶向染色质结构维持蛋白 3 (Structural Maintenance of Chromosomes 3,SMC3),SMC3的去乙酰化对黏连蛋白介导的染色质凝集和姐妹染色体分离具有积极意义[80]。总之,在 HATs 和 HDACs 协同影响下,组蛋白乙酰化成为哺乳动物卵母细胞表观遗传修饰网络中的重要环节。

  • 3.3 组蛋白单泛素化

  • PcG 蛋白家族的另一成员 PRC1 是组蛋白 H2A 亚基 119 号赖氨酸单泛素化 (Histone H2AK119 Mono-ubiquitylation, H2AK119ub1) 的催化酶[81]。 PRC1 的功能核心包括具有 E3 泛素连接酶活性的 RING1A 或 RING1B 以及 1 种多梳环指蛋白 (Polycomb Group Ring Finger,PCGF)。根据组分种类不同,可将 PRC1 进一步区分为含有色素盒 (Chromo Box,CBX) 蛋白的经典 PRC1 (canonical PRC1,cPRC1),以及含有 RING1-YY1 结合蛋白 (RING1 and YY1 Binding Protein, RYBP) 或 YY1 相关因子 2 (YY1 Associated Factor 2,YAF2) 的变体PRC1 (variant PRC1,vPRC1) [8283]。先前研究认为, PRC2 被募集到 CGIs 并建立 H3K27me3 后, cPRC1才在CBX亚基的帮助下识别H3K27me3并催化 H2AK119ub1 的形成与积累[84];然而最近的研究表明,KDM2B 中的 CxxC 结构域可以帮助 PCGF1-vPRC1 复合体首先在靶序列建立 H2AK119ub1,进而被 PRC2 识别并建立 H3K27me3,这种现象在 mESCs 中得到了很好的证明[5185]。总体来说,靶基因的转录沉默机制建立需要 PRC1 和 PRC2 协同配合完成。

  • 在小鼠 FGOs 中,H2AK119ub1 的分布与位于 PMDs 上广泛而低富集的 H3K27me3 重合度很高,而其专一性高富集的区域则与启动子上的 H3K4me3呈现强相关性,这暗示H2AK119ub1与基因的转录激活和抑制均有偶联关系 (见图2)。敲除 FGOs 中 vPRC1 的两个重要亚基 PCGF1 和 PCGF6 后,仅影响部分 H3K27me3 在印迹基因上的建立,且这种改变可遗传到植入前胚胎期并导致相关印迹基因表达异常[86]。相应地,在卵母细胞中消除 PRC2的关键组分胚胎外胚层发育蛋白 (Embryonic Ectoderm Development,EED) 可导致 H3K27me3 缺失,虽然并不影响植入前胚胎中全基因组上 H2AK119ub1 的维持,但阻止了其在 H3K27me3 标记的非经典印迹基因上的重建。此外,由于 H2AK119ub1在受精后胚胎基因启动子上的富集可持续至植入前,因此,相比 H3K27me3,H2AK119 ub1虽然不是非经典印迹基因维持的必要因素,但对于发育基因的转录沉默调控具有不可或缺的作用[87]

  • 3.4 组蛋白磷酸化

  • 磷酸化 (Phosphorylation) 是蛋白质 PTMs中最常见的形式之一。Vlastaridis 等[88] 对磷酸化蛋白组学数据集进行过滤筛选和模拟计算,预测小鼠和人中存在的磷酸化蛋白质分别有 11 000 种和 13 000 种。其中,H3 组蛋白的丝氨酸、苏氨酸和酪氨酸残基可在蛋白激酶 (Protein Kinase,PK) 的介导下发生磷酸化,进而影响基因表达、细胞周期调控、 DNA损伤修复和细胞不对称分裂[60]

  • 机制上,磷酸化可通过改变底物蛋白结构或调节静电环境来操纵蛋白质的活性、定位和作用[89]。这些结果表明,磷酸化修饰在蛋白质广泛参与各类生物学事件中扮演重要角色。以组蛋白 H3 亚基 3 号苏氨酸磷酸化 (Histone H3T3 phosphorylation, H3T3ph) 为例,研究人员在小鼠卵母细胞中发现,在组蛋白 H3 相关蛋白激酶(Histone H3 Associated Protein Kinase,HASPIN)催化作用下,H3T3ph 的表达水平在GVBD期向MⅠ期转换过程中逐渐升高并达到峰值,随后在MⅡ期急剧下降。免疫荧光结果进一步表明,H3T3ph 信号在 GVBD 后的凝缩染色体上强烈富集;到MⅡ期,姐妹染色单体动粒间区域可观察到 H3T3ph 的特异性定位。使用 Haspin 抑制剂 5-ITu 处理 GVOs 可造成其减数分裂恢复阻滞且几乎无法发育至 MⅡ时期;而 MⅠ期 H3T3ph 的缺失会诱导卵母细胞向 MⅡ期过早转换。因此, H3T3ph 不仅可以调控卵母细胞减数分裂过程中同源染色体的分离,还参与纺锤体组装检验点行使功能[9091]。此外,近期研究报道发现,淋巴细胞特异性解旋酶 (Lymphocyte-Specific Helicase,LSH) 缺失可导致卵母细胞内 H3T3ph 水平显著增高和动粒结构异常[92]

  • 3.5 组蛋白乳酸化

  • 乳酸是糖酵解途径中的标志性含碳代谢产物,其生物学功能由于癌细胞 Warburg效应的发现而受到广泛关注。有趣的是,乳酸不仅是循环代谢中的能量底物,还可作为供体为组蛋白氨基酸残基添加乳酸基团,这一特征与乙酰辅酶A(acetyl Coenzyme A,acetyl-CoA) 非常相似。2019 年,Zhang 等[93] 首次发现组蛋白赖氨酸乳酸化 (Lysine lactylation, Kla) 修饰,并在小鼠和人细胞系的核心组蛋白中鉴定出 28 个乳酸化位点。此外,该研究团队发现组蛋白 H3 亚基 18 号赖氨酸乳酸化 (Histone H3K8 lactylation,H3K18la) 可直接促进基因转录并调控巨噬细胞 MⅠ极化。随后,多项工作报道了 Kla在体细胞重编程和细胞命运决定[94]、神经元活动诱导[95] 以及肿瘤发生[96] 等诸多方面发挥调控功能的证据。

  • 在哺乳动物生殖活动中,Yang 等[97] 发现小鼠 GVOs和植入前胚胎中均存在H3K18la、H3K23la以及泛组蛋白乳酸化的荧光信号富集,而MⅡ期卵母细胞中仅发生了 H3K23la 和泛组蛋白乳酸化。另外,该研究结果表明,组蛋白乳酸化与早期胚胎细胞中的乳酸水平呈正相关,且低氧环境会降低组蛋白乳酸化水平从而对植入前胚胎的发育潜力造成负面影响。这表明 Kla可能参与卵母细胞成熟和氧浓度依赖的早期胚胎发育过程。Lin 等[98] 的研究进一步指出,随着 GVOs发育成熟,细胞核内的染色质发生凝集,构型由非环绕核仁 (Non-Surrounding Nucleolus, NSN) 转变为环绕核仁 (Surrounding Nucleolus,SN),此过程中H3K18la、H4K12la以及泛组蛋白乳酸化水平呈现逐渐增高的趋势。此外,由转录因子激活蛋白 2a (Transcription Factor Activating Protein 2a,TFAP2A) 表达水平异常增高引起的纺锤体和染色质缺陷是卵母细胞质量下降的风险来源之一,而过表达 Tfap2a 可导致 H3K18la、 H4K12la以及泛组蛋白乳酸化水平急剧升高,暗示 TFAP2A 调控下的组蛋白乳酸化与卵母细胞纺锤体组装和染色体凝集等关键的发育事件具有潜在关联。

  • 4 总结与展望

  • 卵母细胞作为哺乳动物中极其特殊的一种细胞类群,承载了孕育新个体的重大使命。近年来,随着表观遗传学研究的不断深入和相关技术手段的飞速发展,研究者逐渐揭开了卵母细胞发育过程中表观遗传修饰动态变化的神秘面纱。DNA 甲基化是最早被发现,也是研究最为深入的表观遗传调控机制。PGCs 向生殖嵴迁移的过程往往伴随全基因组去甲基化,这对于卵母细胞中的 DNA 甲基化重塑是必不可少的。此外,组蛋白为 DNA 缠绕形成染色质提供了可靠的物质支持,其表观遗传修饰通常与 DNA 甲基化协同发挥基因转录活性调节和印迹基因标记等生物功能。

  • 基于在哺乳动物卵母细胞中观测到的大量表观遗传调控事件,涌现出诸多有趣的问题。例如,小鼠卵母细胞中 ncH3K4me3的定位几乎完全与 PMDs 重叠,二者之间的强相关性表明组蛋白修饰的重编程与 DNA 甲基化是直接相关的,那么在全基因组上不同区域的 DNA 甲基化和组蛋白修饰联合建立的调控机制是什么?不同组蛋白修饰尽管被证明与转录激活或抑制相关,但它们之间存在功能代偿或冗余的机制和作用是什么?此外,染色质重塑也是表观遗传修饰的重要组成部分。染色质重塑复合物 (Chromatin Remodeling Complex, CRC) 可以 ATP 依赖的方式打破核小体中 DNA 和组蛋白之间的相互作用,从而实现染色质结构特征的改变。虽然已有大量研究解析了这些超复合体的结构和亚基组成,但需要进一步探究其在组蛋白修饰与核小体重新定位中的功能机制,及其在表观遗传调控网络中的作用。不可忽略的是,Hi-C 等测序技术的发展能够帮助科研人员量化基因组染色质间的交联,从而在高维度视角下描绘全基因组互作图谱。

  • 综上所述,未来随着多角度多层次技术手段的开发和应用,我们将不断完善对哺乳动物卵母细胞独特表观遗传景观及其调控网络的认识,为生殖表观遗传的机理研究和相关重大疾病的诊疗提供新的见解和思路。

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