Parental-to-embryo switch of chromosome organization in early embryogenesis
Parental-to-embryo switch of chromosome organization in early embryogenesis
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DOI：
10.1038/s41586-020-2125-z
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发表时间：
2020-03-25
期刊：
影响因子：
64.8
通讯作者：
Heard, Edith
中科院分区：
文献类型：
--
作者：
Collombet, Samuel;Ranisavljevic, Noemie;Heard, Edith
单细胞等位基因 HiC 分析，结合等位基因表达和染色质状态，揭示了小鼠植入前发育过程中染色体组织和基因表达的亲本特异性动态。受精后，父本和母本表观基因组发生显着变化 (1)。最近的表观基因组研究揭示了卵母细胞、精子和早期植入前胚胎中存在的不寻常的染色质景观，包括组蛋白修饰的非典型模式 (2-4) 以及配子 (5-8) 和受精后 (5,8-10) 中染色体组织和可及性的差异。然而，这些研究得出了截然不同的结论：配子中局部拓扑相关结构域 (TAD) 的整体缺失及其在胚胎中的出现 (8,9)，而受精卵中则预先存在 TAD 和环 (5,11)。亲本结构是否可以在新形成的胚胎中遗传以及这些结构如何与等位基因特异性基因调控相关的问题仍然悬而未决。在这里，我们在小鼠植入前使用优化的单细胞高通量染色体构象捕获 (HiC) 方案 (12,13) 绘制每个亲本基因组（包括 X 染色体）的基因组相互作用图谱。我们将染色体组织与等位基因表达状态和染色质标记整合，并揭示受精后的高阶染色质结构与组蛋白 H3 在赖氨酸 27 处甲基化的等位基因特异性富集相一致。这些早期亲本特异性结构域与基因抑制相关并参与亲本偏向基因表达 - 包括最近描述的瞬时印记位点 (14)。我们还发现 TAD 在第二波基因组组装过程中以非亲本特异性方式出现。这些从头结构域与活性染色质相关。最后，我们通过研究植入前雌性胚胎 X 染色体失活之前和期间父本 X 染色体的结构变化，深入了解 TAD 与基因表达之间的关系 (15)。我们发现，当父系 X 染色体上的基因沉默时，TAD 就会丢失，但会停留在逃避 X 染色体失活的区域。这些发现证明了早期发育过程中三维基因组组织和基因表达的复杂动态。
Single-cell allelic HiC analysis, combined with allelic gene expression and chromatin states, reveals parent-of-origin-specific dynamics of chromosome organization and gene expression during mouse preimplantation development.Paternal and maternal epigenomes undergo marked changes after fertilization(1). Recent epigenomic studies have revealed the unusual chromatin landscapes that are present in oocytes, sperm and early preimplantation embryos, including atypical patterns of histone modifications(2-4) and differences in chromosome organization and accessibility, both in gametes(5-8) and after fertilization(5,8-10). However, these studies have led to very different conclusions: the global absence of local topological-associated domains (TADs) in gametes and their appearance in the embryo(8,9) versus the pre-existence of TADs and loops in the zygote(5,11). The questions of whether parental structures can be inherited in the newly formed embryo and how these structures might relate to allele-specific gene regulation remain open. Here we map genomic interactions for each parental genome (including the X chromosome), using an optimized single-cell high-throughput chromosome conformation capture (HiC) protocol(12,13), during preimplantation in the mouse. We integrate chromosome organization with allelic expression states and chromatin marks, and reveal that higher-order chromatin structure after fertilization coincides with an allele-specific enrichment of methylation of histone H3 at lysine 27. These early parental-specific domains correlate with gene repression and participate in parentally biased gene expression-including in recently described, transiently imprinted loci(14). We also find TADs that arise in a non-parental-specific manner during a second wave of genome assembly. These de novo domains are associated with active chromatin. Finally, we obtain insights into the relationship between TADs and gene expression by investigating structural changes to the paternal X chromosome before and during X chromosome inactivation in preimplantation female embryos(15). We find that TADs are lost as genes become silenced on the paternal X chromosome but linger in regions that escape X chromosome inactivation. These findings demonstrate the complex dynamics of three-dimensional genome organization and gene expression during early development.