Hiratani Ichiro, Leskovar Amanda, Gilbert David M
Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16861-6. doi: 10.1073/pnas.0406687101. Epub 2004 Nov 19.
The replication timing of some genes is developmentally regulated, but the significance of replication timing to cellular differentiation has been difficult to substantiate. Studies have largely been restricted to the comparison of a few genes in established cell lines derived from different tissues, and most of these genes do not change replication timing. Hence, it has not been possible to predict how many or what types of genes might be subject to such control. Here, we have evaluated the replication timing of 54 tissue-specific genes in mouse embryonic stem cells before and after differentiation to neural precursors. Strikingly, genes residing within isochores rich in GC and poor in long interspersed nuclear elements (LINEs) did not change their replication timing, whereas half of genes within isochores rich in AT and long interspersed nuclear elements displayed programmed changes in replication timing that accompanied changes in gene expression. Our results provide direct evidence that differentiation-induced autosomal replication-timing changes are a significant part of mammalian development, provide a means to predict genes subject to such regulation, and suggest that replication timing may be more related to the evolution of metazoan genomes than to gene function or expression pattern.
一些基因的复制时间受到发育调控，但其对细胞分化的意义却难以证实。相关研究大多局限于比较源自不同组织的已建立细胞系中的少数基因，而这些基因中的大多数并不会改变复制时间。因此，无法预测有多少基因或哪些类型的基因可能受这种调控。在此，我们评估了小鼠胚胎干细胞在分化为神经前体细胞前后54个组织特异性基因的复制时间。引人注目的是，位于富含GC且长散在核元件（LINEs）较少的等密度区的基因，其复制时间没有改变，而位于富含AT和长散在核元件的等密度区内的基因，有一半显示出复制时间的程序性变化，且这种变化与基因表达的变化相伴。我们的结果提供了直接证据，表明分化诱导的常染色体复制时间变化是哺乳动物发育的重要组成部分，提供了一种预测受此类调控基因的方法，并表明复制时间可能与后生动物基因组的进化关系更大，而非与基因功能或表达模式相关。
