Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals

By M. Guttman, Ido Amit, Manuel Garber, Courtney E. French, Michael F. Lin, D. Feldser, Maite Huarte, Or Zuk, Bryce W. Carey, John P. Cassady and 10 more. Nature, 2009

4,137 citations recorded by the source corpus.

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, NFκB, 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e1116b11942edae6ecd28bea3964459a3443e8bc

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

RNA Sequencing and Analysis (2015, neutral): “A myriad of molecular functions have been discovered for lncRNAs, including chromatin remodeling, transcriptional control, and posttranscriptional processing, although the vast majority are not fully characterized (Guttman et al. 2009; Mercer et al. 2009; Wilusz et al. 2009).”
Transcriptional Regulation by Nrf2 (2017, background): “Some of these binding sites could be located in the promoter region of long non-coding RNAs (lncRNAs), which were beginning to be annotated when Nrf2 binding sites were first profiled (44).”
Epigenetics and gene expression (2010, background): “The consistency of these findings in species as diverse as yeast, human and mouse has allowed the use of histone modification ‘signatures’ to search for novel transcribed genes (Ozsolak et al., 2008; Won et al., 2008; Guttman et al., 2009; Heintzman et al., 2007, 2009).”
Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration (2012, positive): “The next major application of IGV, visualization of ChIP-seq data from whole-genome sequences to find de novo long intergenic noncoding RNAs (lincRNAs) [7], provided motivation to extend the data size limit even further.”
KaKs_Calculator 3.0: Calculating Selective Pressure on Coding and Non-coding Sequences (2021, background): “Albeit less conserved 55 by comparison with coding sequences, a larger number of non-coding sequences have been 56 identified highly conserved across mammalian genomes [8-10].”
Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs (2013, neutral): “tethered together by nonconserved sequence [25,31,32].”
Circular intronic long noncoding RNAs. (2013, background): “The recent advent of high-throughput approaches has revealed that a large portion of the mammalian genome is transcribed into long noncoding RNAs (lncRNAs, >200 nt in length), including thousandsof lincRNAs identifiedusinga ‘‘H3K4me3-H3K36me3’’ chromatin signature of actively transcribed genes (Gutt”
The Xist lncRNA exploits three-dimensional genome architecture to spread across the X-chromosome (2013, background): “Mammalian genomes encode thousands of large non-coding RNAs (lncRNAs) (1-5), many of which play key functional roles in the cell (6-9).”
CpG islands and the regulation of transcription. (2011, background): “A subset of intergenic H3K4me3 peaks (;1600), many of which are likely to correspond to orphan CGIs, were found to represent TSSs for long ncRNAs (Guttman et al. 2009).”
Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution (2015, background): “(3) We sorted each of the two subsets by (a) expression level, (b) tissue specificity, (c) transcript length, (d) the presence of a chromatin signature of actively transcribed genes [1, 3], and (e) being a divergent transcript.”