Publication Date:
2011-03-23
Description:
The genome is extensively transcribed into long intergenic noncoding RNAs (lincRNAs), many of which are implicated in gene silencing. Potential roles of lincRNAs in gene activation are much less understood. Development and homeostasis require coordinate regulation of neighbouring genes through a process termed locus control. Some locus control elements and enhancers transcribe lincRNAs, hinting at possible roles in long-range control. In vertebrates, 39 Hox genes, encoding homeodomain transcription factors critical for positional identity, are clustered in four chromosomal loci; the Hox genes are expressed in nested anterior-posterior and proximal-distal patterns colinear with their genomic position from 3' to 5'of the cluster. Here we identify HOTTIP, a lincRNA transcribed from the 5' tip of the HOXA locus that coordinates the activation of several 5' HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. HOTTIP RNA binds the adaptor protein WDR5 directly and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription. Induced proximity is necessary and sufficient for HOTTIP RNA activation of its target genes. Thus, by serving as key intermediates that transmit information from higher order chromosomal looping into chromatin modifications, lincRNAs may organize chromatin domains to coordinate long-range gene activation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670758/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670758/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Kevin C -- Yang, Yul W -- Liu, Bo -- Sanyal, Amartya -- Corces-Zimmerman, Ryan -- Chen, Yong -- Lajoie, Bryan R -- Protacio, Angeline -- Flynn, Ryan A -- Gupta, Rajnish A -- Wysocka, Joanna -- Lei, Ming -- Dekker, Job -- Helms, Jill A -- Chang, Howard Y -- HG003143/HG/NHGRI NIH HHS/ -- R01 HG003143/HG/NHGRI NIH HHS/ -- R01 HG003143-06/HG/NHGRI NIH HHS/ -- R01 HG003143-06S1/HG/NHGRI NIH HHS/ -- R01 HG003143-06S2/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Apr 7;472(7341):120-4. doi: 10.1038/nature09819. Epub 2011 Mar 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21423168" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line
;
Cells, Cultured
;
Chromatin/*genetics/metabolism
;
DNA, Intergenic/genetics
;
Embryo, Mammalian/metabolism
;
Fibroblasts/metabolism
;
Gene Expression Regulation, Developmental/*genetics
;
Gene Knockdown Techniques
;
Genes, Homeobox/*genetics
;
Histone-Lysine N-Methyltransferase/metabolism
;
Histones/chemistry/metabolism
;
Humans
;
Lysine/metabolism
;
Methylation
;
Mice
;
Molecular Sequence Data
;
Multigene Family/genetics
;
Organ Specificity
;
RNA, Untranslated/*genetics
;
Transcription, Genetic
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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