大型非编码RNA的功能
哺乳动物基因组被转录而产生无数大型非编码RNA，但它们的功能不清楚，主要是因为这些转录体很少或没有演化保守性的证据。
现在，一种对这些神秘分子进行 定性的新方法推动了这一领域的发展。该方法不是以RNA分子本身为目标，相反，它们的存在表现为四种小鼠细胞类型的DNA中的染色质修饰或表观基因组标 记。用该方法进行的搜索工作产生了超过1000个多外显子转录单元，它们与已知的蛋白编码位点不重叠，具有高度保守性。
这些“大型干涉性非编码 RNA”（lincRNAs）中的每一个，都可能有从胚胎干细胞多能性到细胞增殖在内的一定功能。特定lincRNAs是由在包括p53、NFKB、 Sox2、Oct4和Nanog在内的过程中起关键作用的转录因子调控的，而且这些lincRNAs中大多数在不同哺乳动物中都保留了下来。
Nature 458 , 223-227 (12 March 2009) | doi :10.1038/nature07672 ; Received 5 August 2008; Accepted 25 November 2008; Published online 1 February 2009
Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals
Mitchell Guttman 1 , 2 , Ido Amit 1 , Manuel Garber 1 , Courtney French 1 , Michael F. Lin 1 , David Feldser 3 , Maite Huarte 1 , 6 , Or Zuk 1 , Bryce W. Carey 2 , 8 , John P. Cassady 2 , 8 , Moran N. Cabili 7 , Rudolf Jaenisch 2 , 8 , Tarjei S. Mikkelsen 1 , 4 , Tyler Jacks 2 , 3 , Nir Hacohen 1 , 9 , Bradley E. Bernstein 1 , 10 , 11 , Manolis Kellis 1 , 5 , Aviv Regev 1 , 2 , John L. Rinn 1 , 6 , 11 , 12 & Eric S. Lander 1 , 2 , 7 , 8 , 12
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Department of Biology,
The Koch Institute for Integrative Cancer Research,
Division of Health Sciences and Technology, and,
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02114, USA
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
Center for Immunology and Inflammatory Diseases,
Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
These authors contributed equally to this work.
There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts . However, the functional significance of these transcripts has been particularly controversial. Although there are some well-characterized examples, most (>95%) show little evidence of evolutionary conservation and have been suggested to represent transcriptional noise . Here we report a new approach to identifying large non-coding RNAs using chromatin-state maps to discover discrete transcriptional units intervening known protein-coding loci. Our approach identified `1,600 large multi-exonic RNAs across four mouse cell types. In sharp contrast to previous collections, these large intervening non-coding RNAs (lincRNAs) show strong purifying selection in their genomic loci, exonic sequences and promoter regions, with greater than 95% showing clear evolutionary conservation. We also developed a functional genomics approach that assigns putative functions to each lincRNA, demonstrating a diverse range of roles for lincRNAs in processes from embryonic stem cell pluripotency to cell proliferation. We obtained independent functional validation for the predictions for over 100 lincRNAs, using cell-based assays. In particular, we demonstrate that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NF B, Sox2, Oct4 (also known as Pou5f1) and Nanog. Together, these results define a unique collection of functional lincRNAs that are highly conserved and implicated in diverse biological processes.
Full text ：http://www.nature.com/nature/journal/v458/n7235/full/nature07672.html
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