Single-cell landscape of nuclear configuration and gene expression during stem cell differentiation and X inactivation.
Single-cell landscape of nuclear configuration and gene expression during stem cell differentiation and X inactivation.
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DOI：
10.1186/s13059-021-02432-w
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发表时间：
2021-09-27
期刊：
影响因子：
12.3
通讯作者：
Disteche CM
中科院分区：
文献类型：
--
作者：
Bonora G;Ramani V;Singh R;Fang H;Jackson DL;Srivatsan S;Qiu R;Lee C;Trapnell C;Shendure J;Duan Z;Deng X;Noble WS;Disteche CM
哺乳动物的发育与基因表达、染色质可及性和核结构的广泛变化有关。在这里，我们通过整合高通量单细胞RNA-seq、ATAC-seq和Hi-C获得的这三种模式的等位基因特异性数据，首次追踪了与小鼠胚胎干细胞分化和X失活相关的这些变化。通过单细胞Hi-C获得的等位基因特异性接触衰减谱清楚地表明，失活的X染色体在经历X失活的分化细胞中具有独特的谱。这种无活性的x特异性结构在有丝分裂时丢失，随后在细胞周期中重新出现，这表明了一种“书签”机制。胚胎干细胞在X染色体失活后的分化与接触衰减谱的变化有关，这种变化同时发生在X染色体和常染色体上。单细胞RNA-seq和ATAC-seq显示，由于在分化的早期阶段存在两条活跃的X染色体，女性细胞比男性细胞延迟。单细胞中无活性的X特异性结构发生在基因沉默之后，这与染色质压实是X失活的晚期事件的观点一致。单细胞Hi-C强调了核结构离散变化的证据，其特征是整个细胞核获得了非常远距离的接触。新的计算方法允许单细胞基因表达，染色质可及性和3D染色体结构的有效对齐。基于轨迹分析，检测到三种不同的核结构状态，不仅反映了X染色体结构的离散和深刻的同时变化，也反映了常染色体在分化过程中的结构变化。我们的研究表明，染色体的长期结构变化表现为离散事件，不像基因表达和染色质可及性的进行性变化。在线版本包含补充资料，下载地址：10.1186/s13059-021-02432-w。
Mammalian development is associated with extensive changes in gene expression, chromatin accessibility, and nuclear structure. Here, we follow such changes associated with mouse embryonic stem cell differentiation and X inactivation by integrating, for the first time, allele-specific data from these three modalities obtained by high-throughput single-cell RNA-seq, ATAC-seq, and Hi-C. Allele-specific contact decay profiles obtained by single-cell Hi-C clearly show that the inactive X chromosome has a unique profile in differentiated cells that have undergone X inactivation. Loss of this inactive X-specific structure at mitosis is followed by its reappearance during the cell cycle, suggesting a “bookmark” mechanism. Differentiation of embryonic stem cells to follow the onset of X inactivation is associated with changes in contact decay profiles that occur in parallel on both the X chromosomes and autosomes. Single-cell RNA-seq and ATAC-seq show evidence of a delay in female versus male cells, due to the presence of two active X chromosomes at early stages of differentiation. The onset of the inactive X-specific structure in single cells occurs later than gene silencing, consistent with the idea that chromatin compaction is a late event of X inactivation. Single-cell Hi-C highlights evidence of discrete changes in nuclear structure characterized by the acquisition of very long-range contacts throughout the nucleus. Novel computational approaches allow for the effective alignment of single-cell gene expression, chromatin accessibility, and 3D chromosome structure. Based on trajectory analyses, three distinct nuclear structure states are detected reflecting discrete and profound simultaneous changes not only to the structure of the X chromosomes, but also to that of autosomes during differentiation. Our study reveals that long-range structural changes to chromosomes appear as discrete events, unlike progressive changes in gene expression and chromatin accessibility. The online version contains supplementary material available at 10.1186/s13059-021-02432-w.
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