Transcriptional Maps of 10 Human Chromosomes at 5-Nucleotide Resolution

Cheng, Jill; Kapranov, Philipp; Drenkow, Jörg; Dike, Sujit; Brubaker, Shane; Patel, Sandeep; Long, Jeffrey C.; Stern, David L.; Tammana, Hari; Helt, Gregg; Sementchenko, Victor; Piccolboni, Antonio; Bekiranov, Stefan; Bailey, Dione K.; Ganesh, Madhavan; Ghosh, Srinka; Bell, Ian; Gerhard, Daniela S.; Gingeras, T

doi:10.1126/science.1108625

Cited by 1,050 publications

(898 citation statements)

References 32 publications

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“…85 CCAT1 can be detected in CRC tissue and in the blood and stool samples of CRC patients. 86 Thus a CCAT1-based blood/stool assay may be explored for the screening and early detection of CRC. …”

Section: Tumor Diagnosismentioning

confidence: 99%

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

Pan

2014

Modern Pathology

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Long non-coding RNAs (lncRNAs) are a class of newly identified non-coding RNA molecules that are emerging as key regulators of tumor initiation and development. Colorectal cancer (CRC) remains a major health problem worldwide, and there remains a need to further refine the current screening approaches as well as provide tailored diagnostic and therapeutic approaches. Multiple dysregulated lncRNAs participate in tumorigenesis through a variety of molecular mechanisms, and various regulatory factors frequently contribute to the aberrant expression of lncRNAs in CRC, thereby allowing malignant transformation. Additionally, the association of dysregulated lncRNAs with specific developmental stages and clinical outcomes indicates their potential as strong diagnostic and prognostic predictors as well as therapeutic targets. Here we provide a brief overview of the known functions of CRC-associated lncRNAs, describe some potential molecular mechanisms that underlie changes in lncRNA expression in CRC, and attempt to uncover their clinical and therapeutic potential. Keywords: colorectal cancer; diagnosis; dysregulation; long non-coding RNA; prognosis High-throughput genome-scale studies have demonstrated that more than 93% of the DNA sequences in the human genome are actively transcribed. 1 However, only approximately 5-10% of the sequences are stably transcribed into mRNA or non-coding RNA (ncRNA). Genome tiling arrays have revealed that the amount of non-coding sequence is at least four times larger than the amount of coding sequence, which indicates that only 1% of the human genome is composed of protein-coding genes and the remaining 4-9% is transcribed into ncRNAs. 2 Therefore, ncRNAs constitute a very large proportion of the total RNA molecules.The function and clinical significance of short regulatory ncRNAs, such as microRNAs (miRNAs) and small interfering RNAs (siRNAs), were elucidated first, 3 and the regulatory roles of miRNAs have been broadly recognized in almost all physiological and pathological processes in the body, including carcinogenesis. 4 For example, we previously reported that MIR95 promotes cell proliferation and targets sorting nexin 1 in human colorectal carcinoma; 5 moreover, in colorectal cancer (CRC) patients, the plasma levels of MIR29a and MIR92a are significantly upregulated and the plasma levels of MIR601 and MIR760 are significantly downregulated; thus the levels of these miRNAs have good diagnostic value for CRC screening. 6,7 According to their transcript size, ncRNAs are grouped into two major classes: (i) small ncRNAs with transcripts o200 nucleotides (nt; eg, aforementioned siRNAs and miRNAs, Piwi-interacting RNAs, and some retrotransposon-derived RNAs) and (ii) long non-coding RNAs (lncRNAs), this class includes five broad categories: sense, antisense, bidirectional, intronic, and intergenic, based on the proximity between neighboring transcripts. 8 For a time, lncRNAs was commonly defined as a proteincoding transcripts that is 4200 nt. 9 However, this definition is arbitrary and ...

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Section: Tumor Diagnosismentioning

confidence: 99%

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

Pan

2014

Modern Pathology

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“…It should be also kept in mind, however, that all values of gene density must be considered preliminary at present. While most protein coding genes have been identified by now in mouse and human genomes; data from Caenorhabditis elegans suggest that there may be an equally large or even larger number of genes for other types of RNAs (Cheng et al 2005;Ruby et al 2006). It can only be speculated whether such RNA genes are present in similar numbers in vertebrate genomes and if so where their chromosomal location is.…”

Section: Nuclear Positioning and Genomic Propertiesmentioning

confidence: 99%

Three-dimensional positioning of genes in mouse cell nuclei

et al. 2008

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To understand the regulation of the genome, it is necessary to understand its three-dimensional organization in the nucleus. We investigated the positioning of eight gene loci on four different chromosomes, including the β-globin gene, in mouse embryonic stem cells and in in vitro differentiated macrophages by fluorescence in situ hybridization on structurally preserved nuclei, confocal microscopy, and 3D quantitative image analysis. We found that gene loci on the same chromosome can significantly differ from each other and from their chromosome territory in their average radial nuclear position. Radial distribution of a given gene locus can change significantly between cell types, excluding the possibility that positioning is determined solely by the DNA sequence. For the set of investigated gene loci, we found no relationship between radial distribution and local gene density, as it was described for human cell nuclei. We did find, however, correlation with other genomic properties such as GC content and certain repetitive elements such as long terminal repeats or long interspersed nuclear elements. Our results suggest that gene density itself is not a driving force in nuclear positioning. Instead, we propose that other genomic properties play a role in determining nuclear chromatin distribution.

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“…As much as 15% of genomic DNA may be transcribed into RNA, far more than known roles of RNA can explain. 45 With so much cellular RNA of unknown function, some RNAi may affect yetunknown cellular processes. Meantime, experimental reversal of RNAi effects by reexpression of the target protein remains the best sign of specificity.…”

Section: Mechanismsmentioning

confidence: 99%

RNA interference: Natural, experimental, and clinical roles in cancer biology

Mroz¹,

Rocco²

2006

Head Neck

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The old idea of using antisense RNA to block messenger RNA has recently led to powerful new techniques for knocking down expression of individual protein-coding genes. The simplicity and general applicability of these new methods for RNA interference (RNAi) have turned them into fundamental tools in molecular and cellular biology, with more than 5000 publications using them during the few years since they were developed. These experimental methods are now known to exploit fundamental cellular processes that regulate differentiation via genomically encoded RNAi sequences known as microRNAs (miRNAs); changes in endogenous microRNA regulation have now been implicated in oncogenesis. Clinical trials based on local delivery of interfering RNA have already begun. More general methods for safe and effective delivery of interfering RNA to intact organisms are being developed, which could open the way to widespread clinical applications. Because RNAi can provide selective knockdown of almost any protein, it may soon provide an approach to individualized cancer therapy.

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Transcriptional Maps of 10 Human Chromosomes at 5-Nucleotide Resolution

Cited by 1,050 publications

References 32 publications

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

Three-dimensional positioning of genes in mouse cell nuclei

RNA interference: Natural, experimental, and clinical roles in cancer biology

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