scholarly journals Two parallel arms of the heterochronic pathway direct coordinated juvenile-to-adult transition through distinct LIN-29 isoforms

2019 ◽  
Author(s):  
Chiara Azzi ◽  
Florian Aeschimann ◽  
Anca Neagu ◽  
Helge Großhans
Keyword(s):  
Transcription Factor ◽  
Rna Binding ◽  
Binding Protein ◽  
Expression Patterns ◽  
Rna Binding Protein ◽  
Adult Transition ◽  
Physiological Processes ◽  
Regulatory Cascade ◽  
The Individual ◽  
Organismal Development

AbstractRobust organismal development relies on temporal coordination of disparate physiological processes. In Caenorhabditis elegans, the timely transition from juvenile to adult is controlled by the heterochronic pathway, a regulatory cascade of conserved proteins and small RNAs. The heterochronic pathway culminates in accumulation of the transcription factor LIN-29, which triggers coordinated execution of juvenile-to-adult (J/A) transition events. Here, we reveal that two LIN-29 isoforms fulfill distinct functions during the J/A transition. We show that the functional differences between the isoforms do not stem from differences in their sequences, but from their distinct spatiotemporal expression, and we propose that distinct LIN-29 dose sensitivities of the individual J/A transition events help to ensure their temporal ordering. We demonstrate that unique lin-29 isoform expression patterns are generated by the RNA-binding protein LIN-41 for lin-29a, and the transcription factor HBL-1 for lin-29b. By regulating both HBL-1 and LIN-41, the RNA-binding protein LIN-28 coordinates LIN-29 isoform activity. Thus, our findings reveal that a coordinated transition from juvenile to adult involves branching of a linear pathway to achieve timely control of multiple events.

scholarly journals A branched heterochronic pathway directs juvenile-to-adult transition through two LIN-29 isoforms

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chiara Azzi ◽  
Florian Aeschimann ◽  
Anca Neagu ◽  
Helge Großhans
Keyword(s):  
Small Rnas ◽  
Rna Binding ◽  
Expression Patterns ◽  
Functional Specialization ◽  
Adult Transition ◽  
Physiological Processes ◽  
Regulatory Cascade ◽  
Isoform Expression ◽  
The Individual ◽  
Organismal Development

Robust organismal development relies on temporal coordination of disparate physiological processes. In Caenorhabditis elegans, the heterochronic pathway controls a timely juvenile-to-adult (J/A) transition. This regulatory cascade of conserved proteins and small RNAs culminates in accumulation of the transcription factor LIN-29, which triggers coordinated execution of transition events. We report that two LIN-29 isoforms fulfill distinct functions. Functional specialization is a consequence of distinct isoform expression patterns, not protein sequence, and we propose that distinct LIN-29 dose sensitivities of the individual J/A transition events help to ensure their temporal ordering. We demonstrate that unique isoform expression patterns are generated by the activities of LIN-41 for lin-29a, and of HBL-1 for lin-29b, whereas the RNA-binding protein LIN-28 coordinates LIN-29 isoform activity, in part by regulating both hbl-1 and lin-41. Our findings reveal that coordinated transition from juvenile to adult involves branching of a linear pathway to achieve timely control of multiple events.

scholarly journals Polyamines Regulate the Stability of Activating Transcription Factor-2 mRNA through RNA-binding Protein HuR in Intestinal Epithelial Cells

2007 ◽  
Vol 18 (11) ◽  
pp. 4579-4590 ◽  
Author(s):  
Lan Xiao ◽  
Jaladanki N. Rao ◽  
Tongtong Zou ◽  
Lan Liu ◽  
Bernard S. Marasa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Rna Binding ◽  
Binding Protein ◽  
Critical Role ◽  
Rna Binding Protein ◽  
Gene Promoter ◽  
Protein Levels ◽  
Ribonucleoprotein Complexes ◽  
Activating Transcription Factor ◽  
The Stability

Maintenance of intestinal mucosal epithelial integrity requires polyamines that modulate the expression of various genes involved in cell proliferation and apoptosis. Recently, polyamines were shown to regulate the subcellular localization of the RNA-binding protein HuR, which stabilizes its target transcripts such as nucleophosmin and p53 mRNAs. The activating transcription factor-2 (ATF-2) mRNA encodes a member of the ATF/CRE-binding protein family of transcription factors and was computationally predicted to be a target of HuR. Here, we show that polyamines negatively regulate ATF-2 expression posttranscriptionally and that polyamine depletion stabilizes ATF-2 mRNA by enhancing the interaction of the 3′-untranslated region (UTR) of ATF-2 with cytoplasmic HuR. Decreasing cellular polyamines by inhibiting ornithine decarboxylase (ODC) with α-difluoromethylornithine increased the levels of ATF-2 mRNA and protein, whereas increasing polyamines by ectopic ODC overexpression repressed ATF-2 expression. Polyamine depletion did not alter transcription via the ATF-2 gene promoter but increased the stability of ATF-2 mRNA. Increased cytoplasmic HuR in polyamine-deficient cells formed ribonucleoprotein complexes with the endogenous ATF-2 mRNA and specifically bound to 3′-UTR of ATF-2 mRNA on multiple nonoverlapping 3′-UTR segments. Adenovirus-mediated HuR overexpression elevated ATF-2 mRNA and protein levels, whereas HuR silencing rendered the ATF-2 mRNA unstable and prevented increases in ATF-2 mRNA and protein. Furthermore, inhibition of ATF-2 expression prevented the increased resistance of polyamine-deficient cells to apoptosis induced by treatment with tumor necrosis factor-α and cycloheximide. These results indicate that polyamines modulate the stability of ATF-2 mRNA by altering cytoplasmic HuR levels and that polyamine-modulated ATF-2 expression plays a critical role in regulating epithelial apoptosis.

scholarly journals C/EBPα acts as an RNA binding protein essential for its chromatin recruitment and promotes Macrophage differentiation

2021 ◽  
Author(s):  
Yanzhou Zhang ◽  
Mahmoud Bassal ◽  
Daniel Friedrich ◽  
Simone Ummarino ◽  
Tom Verbiest ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Specific Gene ◽  
Macrophage Differentiation ◽  
Binding Domains ◽  
Rna Binding Domains ◽  
Neutrophil Differentiation

C/EBPα has known to be a transcription factor that involved in Neutrophil differentiation for decades. However, exploring the Chromatin RNA Immunoprecipitation Sequencing (RIP), we discover that C/EBPα is a RNA binding protein mainly interacts with RNA introns. Structure study and RNA electrophoretic mobility shift assay (REMSA) show that C/EBPα interacts with RNA through two novel RNA binding domains distinct from its DNA binding domain. Mouse bone marrow transplantation and in vitro cytokine assay reveal that C/EBPα RNA binding is critical for Macrophage differentiation but not Neutrophil differentiation. Mechanically, RNA binding domains control specific gene transcription. In particular, PU.1 intron 4 RNA interacts with C/EBPα and recruit C/EBPα to its enhancer site, which facilitate PU.1 expression. Taken together, C/EBPα is demonstrated to be a RNA binding protein with unique function distinct from its DNA binding activity. Our finding transforms our knowledge of transcriptional regulation by transcription factor.

scholarly journals The multifunctional RNA-binding protein Staufen1: an emerging regulator of oncogenesis through its various roles in key cellular events

2021 ◽  
Author(s):  
Shekoufeh Almasi ◽  
Bernard J. Jasmin
Keyword(s):  
Rna Binding ◽  
Current Knowledge ◽  
Binding Protein ◽  
Neuromuscular Disorders ◽  
Expression Patterns ◽  
Rna Binding Protein ◽  
Rna Metabolism ◽  
Cancer Development ◽  
Cell Functions

AbstractThe double-stranded multifunctional RNA-binding protein (dsRBP) Staufen was initially discovered in insects as a regulator of mRNA localization. Later, its mammalian orthologs have been described in different organisms, including humans. Two human orthologues of Staufen, named Staufen1 (STAU1) and Staufen2 (STAU2), share some structural and functional similarities. However, given their different spatio-temporal expression patterns, each of these orthologues plays distinct roles in cells. In the current review, we focus on the role of STAU1 in cell functions and cancer development. Since its discovery, STAU1 has mostly been studied for its involvement in various aspects of RNA metabolism. Given the pivotal role of RNA metabolism within cells, recent studies have explored the mechanistic impact of STAU1 in a wide variety of cell functions ranging from cell growth to cell death, as well as in various disease states. In particular, there has been increasing attention on the role of STAU1 in neuromuscular disorders, neurodegeneration, and cancer. Here, we provide an overview of the current knowledge on the role of STAU1 in RNA metabolism and cell functions. We also highlight the link between STAU1-mediated control of cellular functions and cancer development, progression, and treatment. Hence, our review emphasizes the potential of STAU1 as a novel biomarker and therapeutic target for cancer diagnosis and treatment, respectively.

scholarly journals RNA Binding Protein, HuR, Regulates SCN5A Expression Through Stabilizing MEF2C transcription factor mRNA

2018 ◽  
Vol 7 (9) ◽  
Author(s):  
Anyu Zhou ◽  
Guangbin Shi ◽  
Gyeoung‐Jin Kang ◽  
An Xie ◽  
Hong Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein

scholarly journals Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

2018 ◽  
Author(s):  
Lisa Fish ◽  
Hoang C.B. Nguyen ◽  
Steven Zhang ◽  
Myles Hochman ◽  
Brian D. Dill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Transcription Factor ◽  
Rna Binding ◽  
Binding Protein ◽  
Intron Retention ◽  
Rna Stability ◽  
Rna Binding Protein ◽  
List Type ◽  
Gene Expression Control

SUMMARYPost-transcriptional regulation of RNA stability is a key step in gene expression control. We describe a regulatory program, mediated by the double-stranded RNA binding protein TARBP2, that controls RNA stability in the nucleus. TARBP2 binding to pre-mRNAs results in increased intron retention, subsequently leading to targeted degradation of TARBP2-bound transcripts. This is mediated by TARBP2 recruitment of the m6A RNA methylation machinery to its target transcripts, where deposition of m6A marks influences the recruitment of splicing regulators, inhibiting efficient splicing. Interactions between TARBP2 and the nucleoprotein TPR then promote degradation of these TARBP2-bound transcripts by the nuclear exosome. Additionally, analysis of clinical gene expression datasets revealed a functional role for this TARBP2 pathway in lung cancer. Using xenograft mouse models, we find that TARBP2 impacts tumor growth in the lung, and that this function is dependent on TARBP2-mediated destabilization of ABCA3 and FOXN3. Finally, we establish the transcription factor ZNF143 as an upstream regulator of TARBP2 expression.RESEARCH HIGHLIGHTSThe RNA-binding protein TARBP2 controls the stability of its target transcripts in the nucleusNuclear TARBP2 recruits the methyltransferase complex to deposit m6A marks on its target transcriptsTARBP2 and m6A-mediated interactions with splicing and nuclear RNA surveillance complexes result in target transcript intron retention and decay.Increased TARBP2 expression is associated with lung cancer and promotes lung cancer growthin vivo.The transcription factor ZNF143 drives oncogenic TARBP2 upregulation in lung cancer.

Sign in / Sign up

Export Citation Format

Share Document