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演題:Replication timing changes and transcriptional regulation during neural differentiation of mouse embryonic stem cells

演者:平谷 伊智朗 博士(Dr. Ichiro Hiratani)
所属:Department of Biochemistry and Molecular Biology&s_comma; SUNY Upstate Medical University&s_comma; NY&s_comma; USA



参考文献:Hiratani&s_comma; I.&s_comma; Leskovar&s_comma; A.&s_comma; and Gilbert&s_comma; D. M. (2004).
Differentiation-induced replication-timing changes are restricted to AT-rich/long interspersed nuclear element (LINE)-rich isochores. Proc Natl Acad Sci U S A 101&s_comma;†16861-16866.

It is generally presumed that replication early in S-phase is a necessary (albeit not sufficient) condition for transcription&s_comma; whereas late-replicating sequences are assembled into transcriptionally inactive chromatin. Thus&s_comma; it was expected that some genes that change their transcription state during cellular differentiation were subject to replication timing changes&s_comma; and indeed we have recently identified many such genes within AT/LINE-rich isochores using a neural differentiation system of mouse embryonic stem (ES) cells (Hiratani et al.&s_comma; 2004&s_comma; PNAS 101:16861).
Here&s_comma; to gain a better understanding of the molecular events surrounding replication timing changes as they occur&s_comma; we have employed a more sophisticated&s_comma; highly homogeneous differentiation system of mouse ES cells (Rathjen et al.&s_comma; 2002&s_comma; Development 129:2649) that recapitulates neurectoderm differentiation in vivo. During a 9-day differentiation to neurectoderm&s_comma; ES-specific genes tested that switch their replication timing from early to late did so in between days 3 and 6&s_comma; in close relation with down-regulation of these genes. Interestingly&s_comma; this is coincident with the loss of pluripotence of ES cells that occurs in between days 5 and 6. On the other hand&s_comma; neurectoderm-specific genes tested that switch from late- to early-replication did so in between days 6 and 9&s_comma; when they become transcriptionally activated and the conversion of definitive ectoderm to neurectoderm occurs. From these observations&s_comma; it is interesting to speculate a close relation between replication timing regulation and cell fate decisions. As studies on a few anectodal genes imply that replication timing switches are regulated at the level of large chromosomal domains&s_comma; our current focus is on a chromosomal region surrounding a neurectoderm-specific gene&s_comma; Pleiotrophin (Ptn)&s_comma; which switches from late to early-replication upon neural differentiation. We have so far identified a 0.5 Mb region surrounding Ptn as the switching domain. Moreover&s_comma; we have observed a remarkable domain-wide transcriptional up-regulation within this 0.5 Mb domain upon differentiation. Because this up-regulation was observed regardless of the sequences being annotated&s_comma; these transcripts could represent non-coding or regulatory RNAs. Hence&s_comma; we seek to further define the nature of these transcripts and their possible link to replication timing changes.

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Masanori Taira&s_comma; Ph.D.
Laboratory of Molecular Biology&s_comma; Department of Biological Sciences Graduate School of Science&s_comma; University of Tokyo Building 2&s_comma; Room 065 7-3-1 Hongo&s_comma; Bunkyo-ku&s_comma; Tokyo 113-8654&s_comma; Japan Phone/FAX: Japan (81) 3-5841-4434

(The following is written in Japanese)
平良 眞規
東京大学 大学院理学系研究科 生物科学専攻 分子生物学研究室
理学部2号館、65号室、113-0033 東京都文京区本郷 7-3-1
電話/FAX:03-5841-4434; 学内から:24434