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- Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). [Guideline]
- AAutophagy 2016; 12(1):1-222
- Transcriptome Analysis of Recurrently Deregulated Genes across Multiple Cancers Identifies New Pan-Cancer Biomarkers. [Journal Article]
- CRCancer Res 2016 Jan 15; 76(2):216-26
- Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gen...
Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression profiles from 225 different cancer cell lines and 339 corresponding primary cell samples to identify transcripts that are deregulated recurrently in a broad range of cancer types. Comparing RNA-seq data from 4,055 tumors and 563 normal tissues profiled in the The Cancer Genome Atlas and FANTOM5 datasets, we identified a core transcript set with theranostic potential. Our analyses also revealed enhancer RNAs, which are upregulated in cancer, defining promoters that overlap with repetitive elements (especially SINE/Alu and LTR/ERV1 elements) that are often upregulated in cancer. Lastly, we documented for the first time upregulation of multiple copies of the REP522 interspersed repeat in cancer. Overall, our genome-wide expression profiling approach identified a comprehensive set of candidate biomarkers with pan-cancer potential, and extended the perspective and pathogenic significance of repetitive elements that are frequently activated during cancer progression.
- Alu RNA regulates the cellular pool of active ribosomes by targeted delivery of SRP9/14 to 40S subunits. [Journal Article]
- NANucleic Acids Res 2015 Mar 11; 43(5):2874-87
- The human genome contains about 1.5 million Alu elements, which are transcribed into Alu RNAs by RNA polymerase III. Their expression is upregulated following stress and viral infection, and they ass...
The human genome contains about 1.5 million Alu elements, which are transcribed into Alu RNAs by RNA polymerase III. Their expression is upregulated following stress and viral infection, and they associate with the SRP9/14 protein dimer in the cytoplasm forming Alu RNPs. Using cell-free translation, we have previously shown that Alu RNPs inhibit polysome formation. Here, we describe the mechanism of Alu RNP-mediated inhibition of translation initiation and demonstrate its effect on translation of cellular and viral RNAs. Both cap-dependent and IRES-mediated initiation is inhibited. Inhibition involves direct binding of SRP9/14 to 40S ribosomal subunits and requires Alu RNA as an assembly factor but its continuous association with 40S subunits is not required for inhibition. Binding of SRP9/14 to 40S prevents 48S complex formation by interfering with the recruitment of mRNA to 40S subunits. In cells, overexpression of Alu RNA decreases translation of reporter mRNAs and this effect is alleviated with a mutation that reduces its affinity for SRP9/14. Alu RNPs also inhibit the translation of cellular mRNAs resuming translation after stress and of viral mRNAs suggesting a role of Alu RNPs in adapting the translational output in response to stress and viral infection.
- Widespread Exonization of Transposable Elements in Human Coding Sequences is Associated with Epigenetic Regulation of Transcription. [Journal Article]
- TOTranscr Open Access 2013 Jun 19; 1(1)
- Transposable Elements (TEs) have long been regarded as selfish or junk DNA having little or no role in the regulation or functioning of the human genome. However, over the past several years this vie...
Transposable Elements (TEs) have long been regarded as selfish or junk DNA having little or no role in the regulation or functioning of the human genome. However, over the past several years this view came to be challenged as several studies provided anecdotal as well as global evidence for the contribution of TEs to the regulatory and coding needs of human genes. In this study, we explored the incorporation and epigenetic regulation of coding sequences donated by TEs using gene expression and other ancillary genomics data from two human hematopoietic cell-lines: GM12878 (a lymphoblastoid cell line) and K562 (a Chronic Myelogenous Leukemia cell line). In each cell line, we found several thousand instances of TEs donating coding sequences to human genes. We compared the transcriptome assembly of the RNA sequencing (RNA-Seq) reads with and without the aid of a reference transcriptome and found that the percentage of genes that incorporate TEs in their coding sequences is significantly greater than that obtained from the reference transcriptome assemblies using Refseq and Gencode gene models. We also used histone modifications chromatin immunoprecipitation sequencing (ChIP-Seq) data, Cap Analysis of Gene Expression (CAGE) data and DNAseI Hypersensitivity Site (DHS) data to demonstrate the epigenetic regulation of the TE derived coding sequences. Our results suggest that TEs form a significantly higher percentage of coding sequences than represented in gene annotation databases and these TE derived sequences are epigenetically regulated in accordance with their expression in the two cell types.
- Chemical approaches for structure and function of RNA in postgenomic era. [Journal Article]
- JNJ Nucleic Acids 2012; 2012:369058
- In the study of cellular RNA chemistry, a major thrust of research focused upon sequence determinations for decades. Structures of snRNAs (4.5S RNA I (Alu), U1, U2, U3, U4, U5, and U6) were determine...
In the study of cellular RNA chemistry, a major thrust of research focused upon sequence determinations for decades. Structures of snRNAs (4.5S RNA I (Alu), U1, U2, U3, U4, U5, and U6) were determined at Baylor College of Medicine, Houston, Tex, in an earlier time of pregenomic era. They show novel modifications including base methylation, sugar methylation, 5'-cap structures (types 0-III) and sequence heterogeneity. This work offered an exciting problem of posttranscriptional modification and underwent numerous significant advances through technological revolutions during pregenomic, genomic, and postgenomic eras. Presently, snRNA research is making progresses involved in enzymology of snRNA modifications, molecular evolution, mechanism of spliceosome assembly, chemical mechanism of intron removal, high-order structure of snRNA in spliceosome, and pathology of splicing. These works are destined to reach final pathway of work "Function and Structure of Spliceosome" in addition to exciting new exploitation of other noncoding RNAs in all aspects of regulatory functions.
- A differential sequencing-based analysis of the C. elegans noncoding transcriptome. [Journal Article]
- RNARNA 2012; 18(4):626-39
- Noncoding RNAs are increasingly being recognized as important players in eukaryote biology. However, despite major efforts in mapping the Caenorhabditis elegans transcriptome over the last couple of ...
Noncoding RNAs are increasingly being recognized as important players in eukaryote biology. However, despite major efforts in mapping the Caenorhabditis elegans transcriptome over the last couple of years, nonpolyadenylated and intermediate-size noncoding RNAs (is-ncRNAs) are still incompletely explored. We have combined an enzymatic approach with full-length RNA-Seq of is-ncRNAs in C. elegans. A total of 473 novel is-ncRNAs has been identified, of which a substantial fraction was associated with transcription factor binding sites and developmentally regulated expression patterns. Analysis of sequence and secondary structure permitted classification of more than 200 is-ncRNAs into several known RNA classes, while another 33 is-ncRNAs were identified as belonging to two previously uncharacterized groups of is-ncRNAs. Three of the unclassified is-ncRNAs contain the 5' Alu domain common to SRP RNAs and specifically bound with the SRP9/14 heterodimer in vitro. One of these (inc394) showed 65% sequence identity with the human, neuron-specific BC200 RNA. Structure-based clustering analysis and in vitro binding experiments supported the notion that the nematode stem-bulge RNAs (sbRNAs) are homologs (or functional analogs) of the Y RNAs. Moreover, analysis of the differential libraries showed that some mature snoRNAs undergo secondary 5' cap modification after processing of the primary transcript, thus suggesting the existence of a wider range of functional RNAs arising from processed and modified fragments of primary transcripts.
- Diversity of contactin mRNA in human brain tumors. [Journal Article]
- MCMol Carcinog 2006; 45(10):774-85
- In order to address the molecular signature of human glioma, we investigated the polymorphism of 5'UTR of the mRNA of Contactin, an adhesion molecule which plays a role in the invasive behavior of th...
In order to address the molecular signature of human glioma, we investigated the polymorphism of 5'UTR of the mRNA of Contactin, an adhesion molecule which plays a role in the invasive behavior of these tumors. Contactin mRNA is identified by RT-PCR and a strategy based on rapid amplification of cDNA ends (RACE) reveals different 5'UTRs resulting from both an alternative use of two types of leader exons and a splicing mechanism within the 5'UTR. The spliced exon is an Alu-containing element specific to the primate lineage, thus indicating a recent evolution of regulatory processes specific to the simian line that occurs on this gene. Each 5'UTR exhibits different transcription/translation efficiencies and contains features that allow translation to occur independently of the classic cap-dependent mechanism. These data illustrate the complex regulation of Contactin expression in human brain tumors occurring at both transcriptional and translation levels. The different 5'UTRs are differentially expressed in diverse types of human tumors. Thus, the polymorphism occurring within the non-coding part of the Contactin mRNA reveals new opportunities to explore deregulation that occurs during the oncogenic process.
- Genomic organization and promoter analysis of the human nicotinic acetylcholine receptor alpha6 subunit (CHNRA6) gene: Alu and other elements direct transcriptional repression. [Journal Article]
- GENEGene 2002 Sep 18; 298(1):101-8
- Nicotinic acetylcholine receptors (nAChRs) form ligand-gated ion channels involved in fast synaptic transmission. Recently mutations in nAChR genes have been reported in nocturnal frontal lobe epilep...
Nicotinic acetylcholine receptors (nAChRs) form ligand-gated ion channels involved in fast synaptic transmission. Recently mutations in nAChR genes have been reported in nocturnal frontal lobe epilepsy. We performed molecular analysis on the human neuronal nAChR alpha6 subunit (CHRNA6) gene, a member of nAChR gene family, to understand its role in disease. Genomic analysis revealed that the gene consisted of six exons with an estimated size of 16 kb. We mapped the CHRNA6 gene to chromosome 8p11.21-11.22 by fluorescence in situ hybridization, the same putative region responsible for adolescent-onset idiopathic generalized epilepsy. Examination of the 5'-regulatory region failed to identify either a TATA box or GC-rich sequences, but did highlight tandem Alu sequences, located between 910 and 370 bp upstream from a potential cap site. Analyses of transcriptional activity, performed using nested deletions of the 5'-upstream region, showed that the downstream Alu repeat and another element(s) in the promoter region, function as negative regulators. Further analyses of the tandem Alu repeats, examined by fusing them to a different ion channel gene promoter, confirmed their role as transcriptional repressors regardless of their orientation and copy number. These data may explain the limited expression of the CHRNA6 gene in the brain.
- Sequence analysis of the human glycoprotein hormone alpha-subunit gene 5'-flanking DNA and identification of a potential regulatory element as an alu repetitive sequence. [Journal Article]
- BBBiochim Biophys Acta 2000 Oct 2; 1493(3):302-18
- The nucleotide sequence of the human glycoprotein hormone alpha-subunit (GPHalpha) gene 5'-flanking DNA was determined from -1637 to +49 relative to the cap site (+1). Comparison of the upstream sequ...
The nucleotide sequence of the human glycoprotein hormone alpha-subunit (GPHalpha) gene 5'-flanking DNA was determined from -1637 to +49 relative to the cap site (+1). Comparison of the upstream sequence of the human gene with those of rhesus and mouse demonstrates regions with variable identity. When the 1.7 kb fragment was used to drive the expression of chloramphenicol acetyltransferase (CAT) in transiently transfected HeLa cells, it was found that CAT activity was elevated about 3-fold when the fragment was truncated from -1637 to -846, suggesting the presence of a negative regulatory element in the distal 5'-flanking DNA. This overlaps an Alu repetitive sequence (ARS) located between nucleotides -1330 and -1007. Gel mobility shift and DNase protection analyses identified a protein binding site centered around -1100 in the ARS second monomer. The GPHalpha upstream ARS was cloned in both orientations in positions upstream and downstream from the bacterial CAT gene under control of the herpes simplex virus thymidine kinase (tk) promoter. DNA-mediated transient transfection of these plasmids revealed a marked inhibition (79-82%) of CAT production by the ARS when it was cloned upstream from the tk promoter and in the same orientation as that found in the GPHalpha 5'-flanking DNA. Smaller decreases (29-57%) were produced by the ARS cloned upstream from the tk promoter in the reverse orientation. In marked contrast, the Alu repetitive element had little or no effect when cloned in either orientation downstream from the tk-CAT gene. Introduction of a second ARS downstream from the CAT reporter gene in vectors already containing an ARS upstream from the tk promoter significantly reduced the strong negative effect elicited by the upstream repetitive element. When compared to the Blur 8 Alu element, the GPHalpha upstream ARS differs markedly with respect to its effect on tk-CAT expression in transient assays and as a substrate for DNA binding proteins present in HeLa nuclear extracts. Together, the transient expression results demonstrate that ARS elements can influence expression of nearby class II promoters. The extent of this effect depends on element position and orientation, cell type, the particular ARS (e.g., GPHalpha or Blur 8), and whether copies were present both upstream and downstream from the transcription unit.
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- Fine-mapping of an ancestral recombination breakpoint in DCP1. [Letter]
- NGenNat Genet 1999; 23(3):270-1