Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types
Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types
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DOI：
10.1101/gr.099655.109
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发表时间：
2010-06-01
期刊：
影响因子：
7
通讯作者：
Gilbert, David M.
中科院分区：
文献类型：
--
作者：
Ryba, Tyrone;Hiratani, Ichiro;Gilbert, David M.
为了确定复制时间的进化保守特征及其与表观遗传特性的关系，我们分析了四种人胚胎干细胞（hESC）系、hESC衍生的神经前体细胞（NPC）、淋巴母细胞和两种人诱导多能干细胞系（hiPSC）的全基因组复制时间，并将其与相关的小鼠细胞类型进行了比较。结果证实了协调复制的兆碱基大小的“复制域”的起源抑制区域打断的保护。分化诱导的复制时间的变化，在这两个物种中发生在400- 800 kb的单位，并同样协调与转录的变化。一个令人惊讶的程度的细胞类型特异性的保护复制时间的保守的同线性的区域，尽管相当大的物种变化的复制时间的排列等容线GC/LINE-1的内容。值得注意的是，hESC的复制时序曲线与小鼠胚胎干细胞（mEpiSC）相比，更显著地对齐。与表观遗传标记的比较揭示了在早期复制域的边界处的染色质修饰的签名，以及通过Hi-C分析测量的复制时间与染色质的空间接近度之间的显著强联系。因此，早期和晚期的复制起始发生在空间上分离的核区室中，但很少发生在间插的染色质中。此外，复制程序的细胞类型特异性保守性意味着染色质空间组织中保守的发育变化。总之，我们的研究结果揭示了哺乳动物发育调节复制程序的进化保守方面，证明了复制分析区分密切相关的细胞类型的能力，并强烈支持复制时序结构域是三维染色体结构的空间区室化结构和功能单元的假设。
To identify evolutionarily conserved features of replication timing and their relationship to epigenetic properties, we profiled replication timing genome-wide in four human embryonic stem cell (hESC) lines, hESC-derived neural precursor cells (NPCs), lymphoblastoid cells, and two human induced pluripotent stem cell lines (hiPSCs), and compared them with related mouse cell types. Results confirm the conservation of coordinately replicated megabase-sized "replication domains" punctuated by origin-suppressed regions. Differentiation-induced replication timing changes in both species occur in 400-to 800-kb units and are similarly coordinated with transcription changes. A surprising degree of cell-type-specific conservation in replication timing was observed across regions of conserved synteny, despite considerable species variation in the alignment of replication timing to isochore GC/LINE-1 content. Notably, hESC replication timing profiles were significantly more aligned to mouse epiblast-derived stem cells (mEpiSCs) than to mouse ESCs. Comparison with epigenetic marks revealed a signature of chromatin modifications at the boundaries of early replicating domains and a remarkably strong link between replication timing and spatial proximity of chromatin as measured by Hi-C analysis. Thus, early and late initiation of replication occurs in spatially separate nuclear compartments, but rarely within the intervening chromatin. Moreover, cell-type-specific conservation of the replication program implies conserved developmental changes in spatial organization of chromatin. Together, our results reveal evolutionarily conserved aspects of developmentally regulated replication programs in mammals, demonstrate the power of replication profiling to distinguish closely related cell types, and strongly support the hypothesis that replication timing domains are spatially compartmentalized structural and functional units of three-dimensional chromosomal architecture.