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Nature Genetics:系统生物学细胞定向分化的关键调控网络

来源:生物通 2009-04-21 13:00

最新一期的Nature Genetics在线版刊登了三篇文章,三个独立的研究团队解决了系统生物学理论中最重要的理论,三文章释放了一系列的数据解答了系统生物学细胞定向分化的关键调控网络。同期Nature配发了评论文章,FANTOM studies networks in cells。

系统生物学研究的最终目的在于解决细胞定向分化的路径,实现这一目标不仅有助人类深入了解整体发育,更有利于人们探索干细胞治疗领域(要实现干细胞治疗目的,首先要掌握干细胞定向分化理论知识和技术)。

这三个独立的研究实验室都属于FANTOM项目的实验室,FANTOM项目旨在深入研究人类基因调控网络。目前全球有100多个实验室参加了这一项目,该项目主要利用RNA测序技术将RNA序列数据与DNA序列数据相比较,鉴定基因转录的起始位点。

本期Nature Genetics上的三篇文章的发布者都属于FANTOM项目实验室,第一个研究小组鉴定出一系列的动物基因转录起始位点,这一研究属于FANTOM4项目,目前已经鉴定了人类,鸡和果蝇的转录起始位点的小RNA,大小在18nt左右。

第二篇文章的研究项目也属于FANTOM4计划,通过全基因组扫描技术鉴定出23000个候选反转录转座子调节序列。功能研究显示,这些反转录转座子的转录调节序列对哺乳动物的转录结果具有重要的影响。

第三篇文章的属于FANTOM4项目,选用人类单核细胞为研究对象,鉴定出人类骨髓性白血病细胞系的转录调控网络。这些研究结果表明,多种转录因子组成复杂的网络,共同调节细胞的生长和分化,没有单个的转录因子唯一的调控因子。(生物谷Bioon.com)

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Nature Genetics 19 April 2009 | doi:10.1038/ng.312

Tiny RNAs associated with transcription start sites in animals

Ryan J Taft1, Evgeny A Glazov2, Nicole Cloonan1, Cas Simons1, Stuart Stephen1, Geoffrey J Faulkner1, Timo Lassmann3, Alistair R R Forrest3,4, Sean M Grimmond1, Kate Schroder1, Katharine Irvine1, Takahiro Arakawa3, Mari Nakamura3, Atsutaka Kubosaki3, Kengo Hayashida3, Chika Kawazu3, Mitsuyoshi Murata3, Hiromi Nishiyori3, Shiro Fukuda3, Jun Kawai3, Carsten O Daub3, David A Hume1,5, Harukazu Suzuki3, Valerio Orlando6,7, Piero Carninci3, Yoshihide Hayashizaki3 & John S Mattick1

It has been reported that relatively short RNAs of heterogeneous sizes are derived from sequences near the promoters of eukaryotic genes. In conjunction with the FANTOM4 project, we have identified tiny RNAs with a modal length of 18 nt that map within -60 to +120 nt of transcription start sites (TSSs) in human, chicken and Drosophila. These transcription initiation RNAs (tiRNAs) are derived from sequences on the same strand as the TSS and are preferentially associated with G+C-rich promoters. The 5' ends of tiRNAs show peak density 10–30 nt downstream of TSSs, indicating that they are processed. tiRNAs are generally, although not exclusively, associated with highly expressed transcripts and sites of RNA polymerase II binding. We suggest that tiRNAs may be a general feature of transcription in metazoa and possibly all eukaryotes.

Nature Genetics 19 April 2009 | doi:10.1038/ng.368

The regulated retrotransposon transcriptome of mammalian cells

Geoffrey J Faulkner1, Yasumasa Kimura2, Carsten O Daub2, Shivangi Wani1, Charles Plessy2, Katharine M Irvine3, Kate Schroder3, Nicole Cloonan1, Anita L Steptoe1, Timo Lassmann2, Kazunori Waki2, Nadine Hornig4,5, Takahiro Arakawa2, Hazuki Takahashi2, Jun Kawai2, Alistair R R Forrest2,6, Harukazu Suzuki2, Yoshihide Hayashizaki2, David A Hume7, Valerio Orlando4,5, Sean M Grimmond1 & Piero Carninci2

Although repetitive elements pervade mammalian genomes, their overall contribution to transcriptional activity is poorly defined. Here, as part of the FANTOM4 project, we report that 6–30% of cap-selected mouse and human RNA transcripts initiate within repetitive elements. Analysis of approximately 250,000 retrotransposon-derived transcription start sites shows that the associated transcripts are generally tissue specific, coincide with gene-dense regions and form pronounced clusters when aligned to full-length retrotransposon sequences. Retrotransposons located immediately 5' of protein-coding loci frequently function as alternative promoters and/or express noncoding RNAs. More than a quarter of RefSeqs possess a retrotransposon in their 3' UTR, with strong evidence for the reduced expression of these transcripts relative to retrotransposon-free transcripts. Finally, a genome-wide screen identifies 23,000 candidate regulatory regions derived from retrotransposons, in addition to more than 2,000 examples of bidirectional transcription. We conclude that retrotransposon transcription has a key influence upon the transcriptional output of the mammalian genome.

Nature Genetics 19 April 2009 | doi:10.1038/ng.375

The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line

The FANTOM Consortium, Riken Omics Science Center1 &

Using deep sequencing (deepCAGE), the FANTOM4 study measured the genome-wide dynamics of transcription-start-site usage in the human monocytic cell line THP-1 throughout a time course of growth arrest and differentiation. Modeling the expression dynamics in terms of predicted cis-regulatory sites, we identified the key transcription regulators, their time-dependent activities and target genes. Systematic siRNA knockdown of 52 transcription factors confirmed the roles of individual factors in the regulatory network. Our results indicate that cellular states are constrained by complex networks involving both positive and negative regulatory interactions among substantial numbers of transcription factors and that no single transcription factor is both necessary and sufficient to drive the differentiation process.

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