Journal Article

A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression

Yang, Yul W., Lajoie, Bryan R., Corces-Zimmerman, Ryan, Lei, Ming, Protacio, Angeline, Helms, Jill A., Wang, Kevin C., Wysocka, Joanna, Dekker, Job, Liu, Bo, Flynn, Ryan A., Chang, Howard Y., Sanyal, Amartya, Chen, Yong, Gupta, Rajnish A.

2011

Overview

Long-range genetic regulation A major question in developmental biology is how functionally related groups of genes are switched on at the right time and in the right place. Long intergenic non-coding RNAs (lincRNAs) have been implicated in both gene silencing and activation, and could be a means of long-range control of gene expression. A lincRNA termed HOTTIP that coordinates the activation of multiple 5' HOXA regulatory genes has now been identified at the 5' tip of the HOXA locus. Chromosomal looping brings HOTTIP close its target genes, where it facilitates histone H3 lysine 4 trimethylation and gene transcription. Long intergenic non-coding RNAs (lincRNAs) have been implicated in both gene silencing and activation, and could be a means for long-range control of gene expression. Here a lincRNA termed HOTTIP is identified at the 5′ tip of the HOXA locus that coordinates the activation of multiple 5′ HOXA genes. Chromosomal looping brings HOTTIP into the proximity of its target genes, where it seems to be required to facilitate histone H3 lysine 4 trimethylation and gene transcription. The genome is extensively transcribed into long intergenic noncoding RNAs (lincRNAs), many of which are implicated in gene silencing 1 , 2 . Potential roles of lincRNAs in gene activation are much less understood 3 , 4 , 5 . Development and homeostasis require coordinate regulation of neighbouring genes through a process termed locus control 6 . Some locus control elements and enhancers transcribe lincRNAs 7 , 8 , 9 , 10 , 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 11 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/200 / 631/337/100 / 631/337/384/2568 / Animals / Biological and medical sciences / Cell differentiation, maturation, development, hematopoiesis / Cell Line / Cell physiology / Cells, Cultured / Chromatin / Chromatin - genetics / Chromatin - metabolism / Chromosomes / Cloning / DNA, Intergenic - genetics / Dynamic programming / Embryo, Mammalian - metabolism / Fibroblasts - metabolism / Fundamental and applied biological sciences. Psychology / Gene expression / Gene Expression Regulation, Developmental - genetics / Gene Knockdown Techniques / Genes, Homeobox - genetics / Genetics / Histone-Lysine N-Methyltransferase - metabolism / Histones - chemistry / Histones - metabolism / Humanities and Social Sciences / Humans / Intracellular Signaling Peptides and Proteins / letter / Lysine - metabolism / Methylation / Mice / Molecular and cellular biology / Molecular Sequence Data / multidisciplinary / Multigene Family - genetics / Organ Specificity / Physiological aspects / Proteins / RNA / RNA polymerase / RNA, Untranslated - genetics / Science / Science (multidisciplinary) / Transcription, Genetic