scholarly journals An integrative ENCODE resource for cancer genomics

2019 ◽  
Author(s):  
Jing Zhang ◽  
Donghoon Lee ◽  
Vineet Dhiman ◽  
Peng Jiang ◽  
Jie Xu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Rna Binding ◽  
Cancer Genomics ◽  
Rna Binding Proteins ◽  
Cell Types ◽  
Whole Genome ◽  
Genome Interpretation ◽  
Network Change ◽  
Tumor Expression ◽  
Opposing Trend

AbstractENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource.

Abstract P351: The Post-transcriptional Regulations Of Centrosomal Plp Mrna In Drosophila

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Junnan Fang
Keyword(s):  
Translational Control ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Types ◽  
Mrna Localization ◽  
Rna Localization ◽  
Embryonic Lethality ◽  
Cellular Processes ◽  
Pericentriolar Material ◽  
And Function

Centrosomes, functioning as microtubule organizing centers, are composed of a proteinaceous matrix of pericentriolar material (PCM) that surrounds a pair of centrioles. Drosophila Pericentrin (Pcnt)-like protein (PLP) is a key component of the centrosome that serves as a scaffold for PCM assembly. The disruption of plp in Drosophila results in embryonic lethality, while the deregulation of Pcnt in humans is associated with MOPD II and Trisomy 21.We recently found plp mRNA localizes to Drosophila embryonic centrosomes. While RNA is known to associate with centrosomes in diverse cell types, the elements required for plp mRNA localization to centrosomes remains completely unknown. Additionally, how plp translation is regulated to accommodate rapid cell divisions during early embryogenesis is unclear. RNA localization coupled with translational control is a conserved mechanism that functions in diverse cellular processes. Control of mRNA localization and translation is mediated by RNA-binding proteins (RBPs). We find PLP protein expression is specifically promoted by an RNA-binding protein, Orb, during embryogenesis; moreover, plp mRNA interacts with Orb. Importantly, we find overexpression of full-length PLP can rescue cell division defects and embryonic lethality caused by orb depletion. We aim to uncover the mechanisms underlying embryonic plp mRNA localization and function and how Orb regulates plp translation.

scholarly journals RNA regulons are essential in intestinal homeostasis

2019 ◽  
Vol 316 (1) ◽  
pp. G197-G204 ◽  
Author(s):  
Louis R. Parham ◽  
Patrick A. Williams ◽  
Priya Chatterji ◽  
Kelly A. Whelan ◽  
Kathryn E. Hamilton
Keyword(s):  
Epithelial Cells ◽  
Rna Binding ◽  
Environmental Changes ◽  
Cell Function ◽  
Rna Binding Proteins ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Cell Dynamics ◽  
Functional Roles ◽  
Proliferating Cell

Intestinal epithelial cells are among the most rapidly proliferating cell types in the human body. There are several different subtypes of epithelial cells, each with unique functional roles in responding to the ever-changing environment. The epithelium’s ability for rapid and customized responses to environmental changes requires multitiered levels of gene regulation. An emerging paradigm in gastrointestinal epithelial cells is the regulation of functionally related mRNA families, or regulons, via RNA-binding proteins (RBPs). RBPs represent a rapid and efficient mechanism to regulate gene expression and cell function. In this review, we will provide an overview of intestinal epithelial RBPs and how they contribute specifically to intestinal epithelial stem cell dynamics. In addition, we will highlight key gaps in knowledge in the global understanding of RBPs in gastrointestinal physiology as an opportunity for future studies.

scholarly journals Deep analysis of RNA N6-adenosine methylation (m6A) patterns in human cells

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Jun Wang ◽  
Liangjiang Wang
Keyword(s):  
Rna Binding ◽  
Data Transfer ◽  
Rna Binding Proteins ◽  
Consensus Sequence ◽  
Model Performance ◽  
Cell Types ◽  
Human Cells ◽  
Rna Modification ◽  
Cell Type ◽  
Cell Type Specific

Abstract N6-adenosine methylation (m6A) is the most abundant internal RNA modification in eukaryotes, and affects RNA metabolism and non-coding RNA function. Previous studies suggest that m6A modifications in mammals occur on the consensus sequence DRACH (D = A/G/U, R = A/G, H = A/C/U). However, only about 10% of such adenosines can be m6A-methylated, and the underlying sequence determinants are still unclear. Notably, the regulation of m6A modifications can be cell-type-specific. In this study, we have developed a deep learning model, called TDm6A, to predict RNA m6A modifications in human cells. For cell types with limited availability of m6A data, transfer learning may be used to enhance TDm6A model performance. We show that TDm6A can learn common and cell-type-specific motifs, some of which are associated with RNA-binding proteins previously reported to be m6A readers or anti-readers. In addition, we have used TDm6A to predict m6A sites on human long non-coding RNAs (lncRNAs) for selection of candidates with high levels of m6A modifications. The results provide new insights into m6A modifications on human protein-coding and non-coding transcripts.

scholarly journals Regulation, diversity and function of MECP2 exon and 3′UTR isoforms

2020 ◽  
Vol 29 (R1) ◽  
pp. R89-R99
Author(s):  
Deivid Carvalho Rodrigues ◽  
Marat Mufteev ◽  
James Ellis
Keyword(s):  
Dna Binding ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Alternative Polyadenylation ◽  
Cell Types ◽  
Protein Isoforms ◽  
Translation Efficiency ◽  
Mrna Isoforms ◽  
Exon 2 ◽  
Messenger Ribonucleic Acid

Abstract The methyl-CpG-binding protein 2 (MECP2) is a critical global regulator of gene expression. Mutations in MECP2 cause neurodevelopmental disorders including Rett syndrome (RTT). MECP2 exon 2 is spliced into two alternative messenger ribonucleic acid (mRNA) isoforms encoding MECP2-E1 or MECP2-E2 protein isoforms that differ in their N-termini. MECP2-E2, isolated first, was used to define the general roles of MECP2 in methyl-deoxyribonucleic acid (DNA) binding, targeting of transcriptional regulatory complexes, and its disease-causing impact in RTT. It was later found that MECP2-E1 is the most abundant isoform in the brain and its exon 1 is also mutated in RTT. MECP2 transcripts undergo alternative polyadenylation generating mRNAs with four possible 3′untranslated region (UTR) lengths ranging from 130 to 8600 nt. Together, the exon and 3′UTR isoforms display remarkable abundance disparity across cell types and tissues during development. These findings indicate discrete means of regulation and suggest that protein isoforms perform non-overlapping roles. Multiple regulatory programs have been explored to explain these disparities. DNA methylation patterns of the MECP2 promoter and first intron impact MECP2-E1 and E2 isoform levels. Networks of microRNAs and RNA-binding proteins also post-transcriptionally regulate the stability and translation efficiency of MECP2 3′UTR isoforms. Finally, distinctions in biophysical properties in the N-termini between MECP2-E1 and E2 lead to variable protein stabilities and DNA binding dynamics. This review describes the steps taken from the discovery of MECP2, the description of its key functions, and its association with RTT, to the emergence of evidence revealing how MECP2 isoforms are differentially regulated at the transcriptional, post-transcriptional and post-translational levels.

scholarly journals ?Cradle?to?grave? regulation of mRNA fate

2007 ◽  
Vol 28 (2) ◽  
pp. 85
Author(s):  
Traude H Beilharz ◽  
Thomas Preiss
Keyword(s):  
Transcription Factors ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Data Sets ◽  
Genome Wide ◽  
Cellular Localisation ◽  
Gene Modules ◽  
Microarray Studies ◽  
Mrna Fate

Microarray studies in Saccharomyces cerevisiae have set the benchmark for genome-wide analyses, available data-sets covering practically every stage of gene expression from DNA-binding by transcription factors to mRNA export, sub-cellular localisation, translation and decay. A theme to emerge from such data has been the prevalence of coordinate gene regulation. Thus, gene modules or ?regulons? are well recognised at the level of gene transcription and the activity of transcription factors provides an obvious molecular explanation for such coordination. More surprising was the organisation of mRNAs into co-regulated ?post-transcriptional operons?. RNA-binding proteins (RBPs), but also ribonucleoprotein (RNP) complexes involving noncoding RNA, have been proposed as the conceptual equivalent of transcription factors at this level.

scholarly journals Structure and functional implications of WYL-domain-containing transcription factor PafBC involved in the mycobacterial DNA damage response

2019 ◽  
Author(s):  
Andreas U. Müller ◽  
Marc Leibundgut ◽  
Nenad Ban ◽  
Eilika Weber-Ban
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Structural Information ◽  
Rna Molecules ◽  
Bacterial Transcription ◽  
Arthrobacter Aurescens

AbstractIn mycobacteria, transcriptional activator PafBC is responsible for upregulating the majority of genes induced by DNA damage. Understanding the mechanism of PafBC activation is impeded by a lack of structural information on this transcription factor that contains a widespread, but poorly understood WYL domain frequently encountered in bacterial transcription factors. Here, we determined the crystal structure ofArthrobacter aurescensPafBC. The protein consists of two modules, each harboring an N-terminal helix-turn-helix DNA binding domain followed by a central WYL and a C-terminal extension (WCX) domain. The WYL domains exhibit Sm-folds, while the WCX domains adopt ferredoxin-like folds, both characteristic for RNA binding proteins. Our results suggest a mechanism of regulation in which WYL domain-containing transcription factors may be activated by binding RNA molecules. Using anin vivomutational screen inMycobacterium smegmatis, we identify potential co-activator binding sites on PafBC.

scholarly journals Protein Factor Requirements of the Apaf-1 Internal Ribosome Entry Segment: Roles of Polypyrimidine Tract Binding Protein and upstream of N-ras

2001 ◽  
Vol 21 (10) ◽  
pp. 3364-3374 ◽  
Author(s):  
Sally A. Mitchell ◽  
Emma C. Brown ◽  
Mark J. Coldwell ◽  
Richard J. Jackson ◽  
Anne E. Willis
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Cell Types ◽  
Polypyrimidine Tract ◽  
Internal Ribosome Entry ◽  
Polypyrimidine Tract Binding ◽  
Polypyrimidine Tract Binding Protein ◽  
Different Cell Types

ABSTRACT It has been reported previously that the 5′ untranslated region of the mRNA encoding Apaf-1 (apoptotic protease-activating factor 1) has an internal ribosome entry site (IRES), whose activity varies widely among different cell types. Here it is shown that the Apaf-1 IRES is active in rabbit reticulocyte lysates, provided that the system is supplemented with polypyrimidine tract binding protein (PTB) and upstream of N-ras (unr), two cellular RNA binding proteins previously identified to be required for rhinovirus IRES activity. In UV cross-linking assays and electrophoretic mobility shift assays with individual recombinant proteins, the Apaf-1 IRES binds unr but not PTB; however, PTB binding occurs if unr is present. Over a range of different cell types there is a broad correlation between the activity of the Apaf-1 IRES and their content of PTB and unr. In cell lines deficient in these proteins, overexpression of PTB and unr stimulated Apaf-1 IRES function. This is the first example where an IRES in a cellular mRNA has been shown to be functionally dependent, both in vitro and in vivo, on specific cellular RNA binding proteins. Given the critical role of Apaf-1 in apoptosis, these results have important implications for the control of the apoptotic cascade.

scholarly journals Structure and functional implications of WYL domain-containing bacterial DNA damage response regulator PafBC

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Andreas U. Müller ◽  
Marc Leibundgut ◽  
Nenad Ban ◽  
Eilika Weber-Ban
Keyword(s):  
Dna Damage ◽  
Transcription Factors ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Structural Information ◽  
Response Regulator ◽  
Bacterial Dna ◽  
Bacterial Transcription ◽  
Arthrobacter Aurescens

Abstract In mycobacteria, transcriptional activator PafBC is responsible for upregulating the majority of genes induced by DNA damage. Understanding the mechanism of PafBC activation is impeded by a lack of structural information on this transcription factor that contains a widespread, but poorly understood WYL domain frequently encountered in bacterial transcription factors. Here, we determine the crystal structure of Arthrobacter aurescens PafBC. The protein consists of two modules, each harboring an N-terminal helix-turn-helix DNA-binding domain followed by a central WYL and a C-terminal extension (WCX) domain. The WYL domains exhibit Sm-folds, while the WCX domains adopt ferredoxin-like folds, both characteristic for RNA-binding proteins. Our results suggest a mechanism of regulation in which WYL domain-containing transcription factors may be activated by binding RNA or other nucleic acid molecules. Using an in vivo mutational screen in Mycobacterium smegmatis, we identify potential co-activator binding sites on PafBC.

scholarly journals NF90/ILF3 is a transcription factor that promotes proliferation over differentiation by hierarchical regulation in K562 erythroleukemia cells

2017 ◽  
Author(s):  
Ting-Hsuan Wu ◽  
Lingfang Shi ◽  
Jessika Adrian ◽  
Minyi Shi ◽  
Ramesh V. Nair ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Rna Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
K562 Cells ◽  
Dna And Rna ◽  
Erythroleukemia Cells ◽  
Binding Factor ◽  
Differential Gene

ABSTRACTNF90 and splice variant NF110 are DNA‐ and RNA-binding proteins encoded by the Interleukin enhancer-binding factor 3 (ILF3) gene that regulate RNA splicing, stabilization and export. The role of NF90 in regulating transcription as a DNA-binding protein has not been comprehensively characterized. Here, ENCODE ChIP-seq identified 9,081 genomic sites specifically bound by NF90/110 in K562 cells. One third of binding sites occurred at promoters of annotated genes. NF90/110 binding colocalized with chromatin marks associated with active promoters and strong enhancers. Comparison with 150 ENCODE ChIP-seq experiments revealed that NF90 clustered with transcription factors exhibiting preference for promoters over enhancers (POLR2A, MYC, YY1). Differential gene expression analysis following shRNA knockdown of NF90 in K562 cells revealed that NF90 directly activates transcription factors that drive growth and proliferation (EGR1, MYC), while attenuating differentiation along erythroid lineage (KLF1). NF90/110 binds chromatin to hierarchically regulate transcription factors to promote proliferation and suppress differentiation.

scholarly journals Characterizing Expression and Regulation of Gamma-Herpesviral Circular RNAs

2021 ◽  
Vol 12 ◽  
Author(s):  
Takanobu Tagawa ◽  
Daniel Oh ◽  
Jerico Santos ◽  
Sarah Dremel ◽  
Guruswamy Mahesh ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Expression Patterns ◽  
Cell Types ◽  
Positive Patient ◽  
Circular Rnas ◽  
Patient Sample

Multiple herpesviruses have been recently found to encode viral circular RNAs. Like cellular circular RNAs, these RNAs lack poly-A tails and their 5′ and 3′ ends have been joined, which confers protection from RNA exonucleases. We examined the expression patterns of circular RNAs from Kaposi’s sarcoma herpesvirus (KSHV) in various environments. We performed deep sequencing of circRNA-enriched total RNA from a KSHV-positive patient lymph node for comparison with previous circRNA-Seq results. We found that circvIRF4 is highly expressed in the KSHV-positive patient sample relative to both B cell lines and de novo infected primary vascular and lymphatic endothelial cells (LECs). Overall, this patient sample showed a viral circRNA expression pattern more similar to the pattern from B cell lines, but we also discovered new back-spliced junctions and additional viral circular RNAs in this patient sample. We validated some of these back-spliced junctions as circular RNAs with standard assays. Differential expression patterns of circular RNAs in different cell types led us to investigate what cellular factors might be influencing the ratio of viral linear mRNAs to circular RNAs. We found that repression of certain RNA-binding proteins shifted the balance between viral linear mRNAs and circular RNAs. Taken together, examining viral circular RNA expression patterns may become useful tools for discovering their functions, the regulators of their expression, and determining the stage and cell types of infection in humans.

Sign in / Sign up

Export Citation Format

Share Document