Regulation Of DNA Replication Timing And Chromatin Three-dimensional Structure During Cell Differentiation

The eukaryotic cell cycle is a complex and highly ordered process.This includes the growth of cells,the replication of genetic material,and the process of separating the chromosomes produced by replication into their daughter cells.DNA replication is a core event in the process.Cell differentiation is the process by which a single cell line produces a series of distinct cell lines with complex structural activities through complex life activities.The selective expression of genes during differentiation requires a specific transcriptional program,and the timing of DNAd replication is closely related to the transcriptional regulation of genes.The cell's biological function is successfully achieved by changing the timing of DNA replication during differentiation.This dynamic change may be closely related to the structure of chromatin.In order to verify this hypothesis,we used high-throughput sequencing data obtained by experimental techniques such as chromosome conformation capture(Hi-C),which are classified into four categories according to the replication timing between embryonic stem cells and somatic cells: The early replication domain,termed CE;the late replication domain,which is conserved in replication in class 5 cells,is called CL;the region that replicates late in stem cells but replicates early in four types of somatic cells,called Lto E;The region that replicates and replicates late in the 4 types of somatic cells is called Eto L.We analyzed the dynamic changes in differentiation and the chromatin properties of conserved regions from the three aspects: chromatin sequence characteristics,epigenetic features and chromatin structural features.First,at the chromatin sequence feature level,the conserved replication domain exhibits chromatin characteristics corresponding to its replication sequence: the early replication domain is the active region with higher gene density,GC content and transposon density,and the late replication domain is The opposite.The regional gene density,GC content,and transposon density of the replication timing were all in the middle of the early and late replication domains.Then,for the chromatin surface,the early replication domain is an euchromatin region enriched with active histone modification signals such as H3K4me3,and the late replication domain is the opposite.The chromatin opening levels of the two types of regions(Eto L and Lto E)in which the replication timing changes in stem cells were comparable,and the modified signal intensities of H3K4me3 and H3K9me3 were also not significantly different.However,after differentiation,it exhibits an apparent characteristic corresponding to the replication timing.Finally,at the chromatin structure module level,the active chromatin that replicates early in the genome has a smaller TAD and a higher level,while the late-replicated chromatin is located at a larger TAD and lower level.For the two types of replication time-series regions,each of them exhibits structural features corresponding to the replication timing in the somatic cells after differentiation,that is,more than half of the replication domains of Eto L are located in B Compartment in the stem cells,and most of them are in the larger TAD.Lto E,on the other hand,is mostly located in A Compartment in stem cells and is in a small TAD.And each of them interacts with the same chromatin more than other chromatin regions.At the transcriptional level,Lto E gene expression is up-regulated and its function corresponds specifically to differentiated cells,which display chromatin status and chromatin structure similar to the conserved early replication genes.Our analysis indicates that different replication domains display different regulatory mechanisms in cell differentiation.DNA replication in the conserved replication domain exhibits temporal and spatial coordination,while DNA replication timing in regions where replication timing changes before and after differentiation are less relevant to Chromatin characteristics and exhibit specific structural features in stem cells.