Open chromatin encoded in DNA sequence is the signature of 'master' replication origins in human cells.
Open chromatin encoded in DNA sequence is the signature of 'master' replication origins in human cells.
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DOI：
10.1093/nar/gkp631
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发表时间：
2009-10
影响因子：
14.9
通讯作者：
Arneodo A
中科院分区：
文献类型：
--
作者：
Audit B;Zaghloul L;Vaillant C;Chevereau G;d'Aubenton-Carafa Y;Thermes C;Arneodo A
多年来，在阐明复制起始及其与转录活性和局部染色质结构耦合的机制方面的进展一直受到人类基因组和更普遍的哺乳动物基因组中确定的起源数量较少（约30个）的阻碍。最近对组成链不对称的计算机研究揭示了人类基因的高水平组织，大约有1000个假定的复制起源。在这里，通过与最近实验确定的复制起源进行比较，我们进一步支持这些假定的起源在体内是活跃的。我们发现，在S期早期复制的大多数这些假定的复制起点周围约300 kb宽的区域对dna酶I切割敏感，低甲基化，并且在损害核小体形成的基因组能量屏障（无核小体区域）中呈现显著富集。这表明，这些假定的复制起源是由DNA序列偏爱的开放染色质结构指定的。我们讨论了这种独特的属性如何使这些起源进一步成为“主”复制起源，成为未来研究破译人类时空复制程序的特权位点。最后，我们认为这些“主”起源可能在进化和病理情况下的基因组动力学中发挥关键作用。
For years, progress in elucidating the mechanisms underlying replication initiation and its coupling to transcriptional activities and to local chromatin structure has been hampered by the small number (approximately 30) of well-established origins in the human genome and more generally in mammalian genomes. Recent in silico studies of compositional strand asymmetries revealed a high level of organization of human genes around 1000 putative replication origins. Here, by comparing with recently experimentally identified replication origins, we provide further support that these putative origins are active in vivo. We show that regions ∼300-kb wide surrounding most of these putative replication origins that replicate early in the S phase are hypersensitive to DNase I cleavage, hypomethylated and present a significant enrichment in genomic energy barriers that impair nucleosome formation (nucleosome-free regions). This suggests that these putative replication origins are specified by an open chromatin structure favored by the DNA sequence. We discuss how this distinctive attribute makes these origins, further qualified as ‘master’ replication origins, priviledged loci for future research to decipher the human spatio-temporal replication program. Finally, we argue that these ‘master’ origins are likely to play a key role in genome dynamics during evolution and in pathological situations.
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