专家点评Emery Bresnick 教授（美国威斯康星大学麦迪逊分校细胞与再生生物学系教授，威斯康星血液癌症研究所主任） The study by Li et al. focused on addressing the higher-order nuclear reorganization during the process in which chromatin condenses in a vital developmental mechanism, the generation of human erythrocytes. This process involves compressing 70-80% of the nuclear volume while maintaining select functions and establishing new functions before enucleation. The surprising finding is that a large number (~60%) of chromatin domains (topologically associating domain, TAD) are disrupted throughout the chromatin condensation process, while cohorts of erythroid genes reside in select essential domains that are maintained until the end of cellular differentiation. Transcriptional competence, which is inferred by marks of the active transcriptional state (including RNA polymerase II and H3K27Ac), and the essential erythroid transcription factor GATA1 are important determinant of this selectivity. Interestingly, their results also reveal that heterochromatin relocalizes to the nuclear periphery and a significant number of long-range interactions among heterochromatin regions are established during chromatin condensation, indicating these regions undergone more drastic reorganization than euchromatin regions.Finally, this study has significance from both fundamental and translational perspectives. Hematological diseases, such as myelodysplastic syndromes and megaloblastic anemia, often exhibit erythroid differentiation defects. While establishment of the three-dimensional chromatin architecture has been studied in the several cell contexts, the mechanisms of chromatin condensation and the associated disruption of higher-order nuclear topology remain elusive. The authors established a primary human erythroid differentiation system to address this question and uncovered fundamental principles governing chromatin condensation and distinct features underlying erythropoiesis. This system constitutes a powerful model to study nuclear topology during development and diseases. 李湘盈团队的研究聚焦于重要发育机制-人类红细胞发育染色质凝集过程中的染色质高级结构改变。此过程涉及压缩70-80%的细胞核体积，同时在脱核前保持和建立特定的新功能。令人惊讶的发现是，大量(~60%)的染色质结构域（拓扑相关结构域，TAD）在整个染色质浓缩过程中被破坏，而红系基因群位于特定的结构与中，这些结构域一直保持完整直到细胞分化结束。活性染色质标记（RNA聚合酶II，和H3K27ac）以及必需的红细胞转录因子GATA1是这种选择性的重要决定因素。有趣的是，他们的结果还表明，染色质压缩过程中异染色质重新定位到细胞核外围，并且在染色质浓缩过程中建立了异染色质区域之间的大量远程相互作用，表明这些区域比常染色质区域经历了更剧烈的重组。 总而言之，这项研究从基础和转化的角度来看都具有重要意义。骨髓增生异常综合征和巨幼红细胞性贫血等血液病常表现出红细胞分化缺陷。虽然三维染色质结构在多种细胞中已经被研究，但染色质浓缩的机制和相关的染色质结构域破坏仍然不清楚。作者建立了一个原代人类红细胞分化系统来解决这个问题，并揭示了红细胞生成中染色质浓缩的基本原则和特征，并且提供了一个发育和疾病中研究染色质高级结构改变的强大模型。 专家点评安秀丽 教授（美国纽约血液中心 膜生物学实验室主任） 红细胞对脊椎动物的氧气输送是不可或缺的，其发育受到精细的调控。红系发育早期阶段的红系祖细胞经过一系列的扩增和分化进入终末阶段形成红系前体细胞。而红系前体细胞在终末发育阶段中会历经血红蛋白合成增加、染色质凝缩、核固缩和脱核等一系列独特的生物学事件，最终形成功能成熟的新生红细胞。红细胞脱核前的染色质凝缩以及最终的脱核过程一直是红细胞发育调控机制研究重点，以及提升体外造血效率的关键。 李湘盈团队利用人类红细胞发育体系及HiC及HiChIP等多种组学技术在分离纯化的早期和晚期成红细胞中解析了红细胞染色质凝缩的规律，发现异染色质的大规模远距离互作是红细胞终末阶段发育过程中染色质结构动态改变的主要特征，并发现与其他细胞分化过程中的显著不同之处：染色质拓扑相关结构域（TAD）大量瓦解。TAD结构的瓦解与CTCF及Cohesin分子的结合减弱相关，此外，该研究还同时发现红细胞中的重要转录因子GATA1参与到红系终末分化过程中的染色质结构域维持以及终末时期红细胞转录态势调控。 该工作为未来研究红细胞终末分化过程中的染色质结构的调控机制提供了有力的数据支撑和理论基础。深入理解红系发育终末阶段染色质结构的特异性变化，可以帮助我们全面理解红细胞的脱核过程及其调控机制。而在该工作的基础上明确GATA1维持TAD结构的分子机制，寻找新的红细胞终末分化调控靶点及提升体外造血特别是脱核效率，将是值得深入探索的重要方向。
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参考文献
1. Dzierzak, E. and S. Philipsen, Erythropoiesis: development and differentiation. Cold Spring Harb Perspect Med, 2013. 3(4): p. a011601.2. Palis, J., Primitive and definitive erythropoiesis in mammals. Front Physiol, 2014. 5: p. 3.3. Sankaran, V.G. and M.J. Weiss, Anemia: progress in molecular mechanisms and therapies. Nat Med, 2015. 21(3): p. 221-30.4. Keerthivasan, G., A. Wickrema, and J.D. Crispino, Erythroblast enucleation. Stem Cells Int, 2011. 2011: p. 139851.