Nature破解系统生物学大难题

http://www.microimage.com.cn(2009-04-21 09:44:37)

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。
原文检索:

Tiny RNAs associated with transcription start sites in animals

【Abstract】

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.

 

The regulated retrotransposon transcriptome of mammalian cells

【Abstract】

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.

 

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

【Abstract】

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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