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

Abstract

The genome is extensively transcribed into long intergenic noncoding RNAs (lincRNAs), many of which are implicated in gene silencing1,2. Potential roles of lincRNAs in gene activation are much less understood3,4,5. Development and homeostasis require coordinate regulation of neighboring genes through a process termed locus control6. Some locus control elements and enhancers transcribe lincRNAs7,8,9,10, 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 co-linear with their genomic position from 3′ to 5′of the cluster11. Here we identify HOTTIP, a lincRNA transcribed from the 5′ tip of the HOXA locus that coordinates the activation of multiple 5′ HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. HOTTIP directly binds the adaptor protein WDR5 and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription. Induced proximity is necessary and sufficient for HOTTIP 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.

Long Non-coding RNAs (LncRNA) Regulated by Transforming Growth Factor (TGF) β

“…4A). Previous studies have shown that the HOX gene clusters (HOXA, HOXB, HOXC, and HOXD) are well conserved across species and several lncRNAs have been shown to be functionally important within these regions (1,12,13).…”

“…Expression of LncRNA-HIT Is Conserved and Is Elevated in Human Invasive Ductal Breast Cancer-LncRNA-HIT resides in the 5Ј distal Hoxa gene cluster, a region of the genome that is highly conserved (12,22). We therefore used BLAST analysis software to evaluate the conservation of lncRNA-HIT in humans and the potential for orthologs residing in the same genomic location.…”

Rôle des longs ARN non codants dans le développement normal et pathologique

“…Les lncRNA peuvent potentiellement lier l'ADN, des protéines ou d'autres ARN, formant des plateformes d'échafaudage et permettant ainsi l'interaction entre diverses molécules fonctionnelles (Figure 4). Certains lncRNA peuvent modifier le contexte chromatinien près de leurs gènes cibles, en recrutant des facteurs de transcription ou des acteurs de la modification d'histones ou de la réorganisation de la chromatine, favorisant ou réprimant ainsi la transcription de gènes cibles, selon le [20,21]. Les lncRNA sont aussi largement impliqués dans les processus post-transcriptionnels liés à la biogenèse des ARNm, tels que l'épissage, le transport, la traduction et la dégradation des ARNm (Figure 4).…”

The activatory long non-coding RNA DBE-T reveals the epigenetic etiology of facioscapulohumeral muscular dystrophy

“…In particular, DBE-T interacts with one of the Trx components, the ASH1L protein, which has also been studied in Drosophila, demonstrating its involvement in the activation of Hox gene expression when it is recruited to Hox regulatory elements by lncRNAs [9]. Wang et al [10] described the first activatory lncRNA in 2011: HOTTIP, a long intergenic non-coding RNA (lincRNA) involved in the production of HOXA genes. Cabianca et al [1] have identified the first lncRNA linked to the Trithorax activation complex in relation to a particular disorder.…”