scholarly journals Conformational Changes in the Negative Arm of the Circadian Clock Correlate with Dynamic Interactomes Involved in Post-transcriptionally Regulated Processes

2021 ◽  
Author(s):  
Jacqueline F Pelham ◽  
Alexander E Mosier ◽  
Samuel C Altshuler ◽  
Christopher L Kirchhoff ◽  
William B Fall ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Circadian Clock ◽  
Conformational Changes ◽  
Transcriptional Activation ◽  
Environmental Changes ◽  
Macromolecular Complex ◽  
Macromolecular Complexes ◽  
Cellular Physiology ◽  
Intrinsically Disordered ◽  
Post Transcriptional Regulation

The circadian clock employs a transcriptional/translational negative feedback loop (TTFL) to anticipate environmental changes due to the Earth′s diurnal cycle, with regulation of organismal physiology believed to stem from temporal transcriptional activation by the positive arm. However, up to 80% of oscillating proteins do not have rhythmic mRNA, establishing circadian post-transcriptional regulation through unknown mechanisms. Given the pervasive conservation of the intrinsically disordered nature of negative-arm clock proteins, we hypothesized that post-transcriptional regulation may stem from conformational shifts in negative-arm proteins that time vacillations in the constituents of negative-arm macromolecular complexes to time cellular physiology. Our investigation of the negative arm clock protein in Neurospora crassa, FREQUENCY (FRQ), demonstrated temporal conformational fluidity correlated with daily changes in physiologically diverse macromolecular complex components. A parallel investigation of the macromolecular complexes centered around Drosophila melanogaster PERIOD (dPER) and human PERIOD (hPER2) found a similar number and physiological diversity of interacting partners in higher eukaryotes. Short linear motifs (SLiMs) associated with the interactors localized to disordered and phosphorylated regions on the PERs and FRQ, with disordered interactors oscillating in the macromolecular complexes over circadian time. This oscillation correlated with oscillations in post-transcriptionally regulated proteins, suggesting the negative arm may tune cellular physiology and proteostasis post-transcriptionally via vacillations in the circadian negative-arm macromolecular protein complexes.

Rhythmic post-transcriptional regulation of the circadian clock protein mPER2 in mammalian cells: A real-time analysis

2006 ◽  
Vol 401 (1-2) ◽  
pp. 44-48 ◽  
Author(s):  
Keigo Nishii ◽  
Iori Yamanaka ◽  
Maya Yasuda ◽  
Yota B. Kiyohara ◽  
Yoko Kitayama ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Circadian Clock ◽  
Real Time ◽  
Mammalian Cells ◽  
Time Analysis ◽  
Real Time Analysis ◽  
Post Transcriptional Regulation ◽  
Clock Protein

scholarly journals All-trans retinoic acid induces GADD34 gene expression via transcriptional regulation by Six1-TLE3 and post-transcriptional regulation by p38-TTP in skeletal muscle

2021 ◽  
Author(s):  
Yuichiro Adachi ◽  
Masashi Masuda ◽  
Iori Sakakibara ◽  
Takayuki Uchida ◽  
Yuki Niida ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Retinoic Acid ◽  
Transcriptional Activation ◽  
Fiber Type ◽  
Gene Promoter ◽  
Unfolded Protein ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Inducible Protein ◽  
Post Transcriptional Regulation

All-trans retinoic acid (ATRA) increases the sensitivity to unfolded protein response (UPR) in differentiating leukemic blasts. The downstream transcriptional factors of PERK, a major arm of UPR, regulates muscle differentiation. However, the role of growth arrest and DNA damage-inducible protein 34 (GADD34), one of the downstream factors of PERK, and the effects of ATRA on GADD34 expression in muscle remain unclear. In this study, we identified ATRA increased the GADD34 expression independent of the PERK signal in the gastrocnemius muscle of mice. ATRA up-regulated GADD34 expression through the transcriptional activation of it via inhibiting the interaction of homeobox Six1 and transcription co-repressor TLE3 with the MEF3-binding site on the GADD34 gene promoter in myoblasts. ATRA also inhibited the interaction of TTP, which induces mRNA degradation, with AU-rich element on GADD34 mRNA via p38 MAPK, resulting in the instability of GADD34 mRNA. Overexpressed GADD34 in myoblasts changes the type of myosin heavy chain in myotubes. These results suggest ATRA increases GADD34 expression via transcriptional and post-transcriptional regulation in myoblasts, which changes muscle fiber type in myotubes.

scholarly journals Abundance of hepatic metallothionein mRNA is increased by protein-synthesis inhibitors. Evidence for transcriptional activation and post-transcriptional regulation

1991 ◽  
Vol 273 (1) ◽  
pp. 185-188 ◽  
Author(s):  
C C McCormick ◽  
L M Salati ◽  
A G Goodridge
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Transcriptional Regulation ◽  
Transcriptional Activation ◽  
Actinomycin D ◽  
Protein Synthesis Inhibitors ◽  
Mrna Accumulation ◽  
Hepatic Metallothionein ◽  
Post Transcriptional Regulation

Ongoing protein synthesis is a prerequisite in the expression of some genes. We studied the effect of various protein synthesis inhibitors on the expression of the avian metallothionein (MT) gene. Chicken embryonic hepatocytes in culture were exposed to various concentrations of cycloheximide, puromycin and pactamycin. At concentrations which decreased total protein synthesis by about 90% each inhibitor increased MT mRNA accumulation approx. 5-fold at 9 h of incubation. Incubation with puromycin or zinc for 2 h markedly increased the rate of MT gene transcription. Estimates of the half-life of MT mRNA by using actinomycin D suggested for cycloheximide, but not puromycin, decreased the decay rate of MT mRNA. These data suggest the potential for post-transcriptional regulation of the avian MT gene. We conclude that different antibiotics increase the accumulation of hepatocyte MT mRNA by different mechanisms and that the possibility of multiple mechanisms should be considered in other studies of the role of protein synthesis in gene expression.

scholarly journals Novel insights into the pervasive role of RNA structure in post-transcriptional regulation of gene expression in plants

2021 ◽  
Vol 49 (4) ◽  
pp. 1829-1839
Author(s):  
Huakun Zhang ◽  
Yiliang Ding
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Rna Structure ◽  
Environmental Changes ◽  
Regulation Of Gene Expression ◽  
Intrinsic Property ◽  
Rna Degradation ◽  
Mrna Maturation ◽  
Recent Developments ◽  
Post Transcriptional Regulation

RNA folding is an intrinsic property of RNA that serves a key role in every step of post-transcriptional regulation of gene expression, from RNA maturation to translation in plants. Recent developments of genome-wide RNA structure profiling methods have transformed research in this area enabling focus to shift from individual molecules to the study of tens of thousands of RNAs. Here, we provide a comprehensive review of recent advances in the field. We discuss these new insights of RNA structure functionality within the context of post-transcriptional regulation including mRNA maturation, translation, and RNA degradation in plants. Notably, we also provide an overview of how plants exhibit different RNA structures in response to environmental changes.

scholarly journals Post-Transcriptional Circadian Regulation in Macrophages Organizes Temporally Distinct Immunometabolic States

2020 ◽  
Author(s):  
Emily J Collins ◽  
Mariana P Cervantes-Silva ◽  
George A Timmons ◽  
James R O’Siorain ◽  
Annie M Curtis ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Metabolic Regulation ◽  
Time Course ◽  
Mitochondrial Morphology ◽  
Circadian Regulation ◽  
Atp Production ◽  
Post Transcriptional Regulation ◽  
The Impact

SUMMARYOur core timekeeping mechanism, the circadian clock, regulates an astonishing amount of cellular physiology and behavior, playing a vital role in organismal fitness. While the mechanics of circadian control over cellular regulation can in part be explained by the transcriptional activation stemming from the positive arm of the clock’s transcription-translation negative feedback loop, research has shown that extensive circadian regulation occurs beyond transcriptional activation in fungal species and data suggest that this post-transcriptional regulation may also be preserved in mammals. To determine the extent to which circadian output is regulated post-transcriptionally in mammalian cells, we comprehensively profiled the transcriptome and proteome of murine bone marrow-derived macrophages in a high resolution, sample rich time course. We found that only 15% of the circadian proteome had corresponding oscillating mRNA and this regulation was cell intrinsic. Ontological analysis of oscillating proteins revealed robust temporal enrichment for protein degradation and translation, providing potential insights into the source of this extensive post-transcriptional regulation. We noted post-transcriptional temporal-gating across a number of connected metabolic pathways. This temporal metabolic regulation further corresponded with rhythms we observed in ATP production, mitochondrial morphology, and phagocytosis. With the strong interconnection between cellular metabolic states and macrophage phenotypes/responses, our work demonstrates that post-transcriptional circadian regulation in macrophages is broadly utilized as a tool to confer time-dependent immune function and responses. As macrophages coordinate many immunological and inflammatory functions, an understanding of this regulation provides a framework to determine the impact of circadian regulation on a wide array of disease pathologies.

scholarly journals Distinct Hypoxia-induced Translational Profiles of Embryonic and Adult-derived Macrophages

2021 ◽  
Author(s):  
Nicholas S. Wilcox ◽  
Timur O. Yarovinsky ◽  
Prakruti Pandya ◽  
Vinod S. Ramgolam ◽  
Albertomaria Moro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Rna Binding ◽  
Environmental Changes ◽  
Rna Binding Proteins ◽  
Fetal Liver ◽  
Affinity Purification ◽  
Regulation Of Gene Expression ◽  
Translation Rate ◽  
Post Transcriptional Regulation

SummaryTissue homeostasis and repair are orchestrated by resident and newly recruited macrophages that alter their gene expression program in response to changes in tissue microenvironment. Embryonic macrophages, such as fetal liver derived macrophages (FLDM) seed the organs, including heart and lung during embryonic development and persist throughout the adult lifetime, while bone marrow-derived macrophages (BMDM) are recruited following an acute perturbation. Transcriptome analyses of FLDM and BMDM identified differences between them at the level of RNA expression, which correlates imperfectly with protein levels. Post-transcriptional regulation by microRNAs (miRNAs) and RNA-binding proteins determines mRNA stability and translation rate and may override transcriptional cues in response to environmental changes, such as hypoxia. To identify distinct features of FLDM and BMDM response to hypoxia at the level of translation, we employed translating ribosome affinity purification (TRAP) to isolate polysomal RNA. RNA-seq profiling of translated RNA identified distinct hypoxia-induced translational signature of BMDM (Ly6e, vimentin and glycolysis-associated enzymes Pgk1, Tpi1, Aldoa, Ldha) and FLDM (chemokines Ccl7 and Ccl2). By translational profiling of BMDM and FLDM with deletion of the RNA-binding protein HuR, we identified transcripts that were dependent on HuR. These findings highlight the importance of HuR and identify its distinct targets for post-transcriptional regulation of gene expression in embryonic vs. adult-derived macrophages.

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