MicroRNAs and post-transcriptional regulation of skeletal development

MicroRNAs (miRNAs) have become integral nodes of post-transcriptional control of genes that confer cellular identity and regulate differentiation. Cell-specific signaling and transcriptional regulation in skeletal biology are extremely dynamic processes that are highly reliant on dose-dependent responses. As such, skeletal cell-determining genes are ideal targets for quantitative regulation by miRNAs. So far, large amounts of evidence have revealed a characteristic temporal miRNA signature in skeletal cell differentiation and confirmed the essential roles that numerous miRNAs play in bone development and homeostasis. In addition, microarray expression data have provided evidence for their role in several skeletal pathologies. Mouse models in which their expression is altered have provided evidence of causal links between miRNAs and bone abnormalities. Thus, a detailed understanding of the function of miRNAs and their tight relationship with bone diseases would constitute a powerful tool for early diagnosis and future therapeutic approaches.

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Regulatory signals in messenger RNA: determinants of nutrient–gene interaction and metabolic compartmentation

British Journal Of Nutrition ◽

10.1017/s0007114598001378 ◽

1998 ◽

Vol 80 (4) ◽

pp. 307-321

Author(s):

John E. Hesketh ◽

M. Helena Vasconcelos ◽

Giovanna Bermano

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Mrna Stability ◽

Transcriptional Control ◽

Regulation Of Gene Expression ◽

Untranslated Regions ◽

Nutritional Requirements ◽

Control Of Gene Expression ◽

Metabolic Compartmentation ◽

Post Transcriptional Regulation

Nutrition has marked influences on gene expression and an understanding of the interaction between nutrients and gene expression is important in order to provide a basis for determining the nutritional requirements on an individual basis. The effects of nutrition can be exerted at many stages between transcription of the genetic sequence and production of a functional protein. This review focuses on the role of post-transcriptional control, particularly mRNA stability, translation and localization, in the interactions of nutrients with gene expression. The effects of both macronutrients and micronutrients on regulation of gene expression by post-transcriptional mechanisms are presented and the post-transcriptional regulation of specific genes of nutritional relevance (glucose transporters, transferrin, selenoenzymes, metallothionein, lipoproteins) is described in detail. The function of the regulatory signals in the untranslated regions of the mRNA is highlighted in relation to control of mRNA stability, translation and localization and the importance of these mRNA regions to regulation by nutrients is illustrated by reference to specific examples. The localization of mRNA by signals in the untranslated regions and its function in the spatial organization of protein synthesis is described; the potential of such mechanisms to play a key part in nutrient channelling and metabolic compartmentation is discussed. It is concluded that nutrients can influence gene expression through control of the regulatory signals in these untranslated regions and that the post-transcriptional regulation of gene expression by these mechanisms may influence nutritional requirements. It is emphasized that in studies of nutritional control of gene expression it is important not to focus only on regulation through gene promoters but also to consider the possibility of post-transcriptional control.

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fushi tarazu protein expression in the cellular blastoderm of Drosophila detected using a novel imaging technique

Development ◽

10.1242/dev.106.1.95 ◽

1989 ◽

Vol 106 (1) ◽

pp. 95-103 ◽

Cited By ~ 2

Author(s):

T.L. Karr ◽

T.B. Kornberg

Keyword(s):

Transcriptional Regulation ◽

Protein Expression ◽

Transcriptional Control ◽

Imaging Technique ◽

Drosophila Embryo ◽

Immunoperoxidase Technique ◽

Fushi Tarazu ◽

Post Transcriptional Regulation ◽

Blastoderm Stage ◽

Anterior Posterior

The fushi tarazu (ftz) gene is essential for segmentation of the Drosophila embryo. This requirement is reflected at the cellular blastoderm stage of embryogenesis by seven transverse stripes of ftz expression. These stripes correspond to the missing segments of ftz mutant embryos. We describe here novel intermediate patterns of ftz protein expression which were detected in younger embryos by using anti-ftz antibodies and a sensitive fluorescence/immunoperoxidase technique (‘filtered fluorescence imaging’, FFI). Striped patterns of ftz protein evolved continuously, and the different stripes appeared in an ordered sequence, involving both anterior-posterior (A/P) and dorsal-ventral (D/V) progressions. Comparison of these patterns of ftz protein with those of ftz RNA suggests that these novel aspects of the patterning process involve post-transcriptional regulation in addition to the transcriptional control known to be involved in expression of this gene.

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H3K36 methyltransferase NSD1 regulates chondrocyte differentiation for skeletal development and fracture repair

Bone Research ◽

10.1038/s41413-021-00148-y ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Rui Shao ◽

Zhong Zhang ◽

Zhan Xu ◽

Huiling Ouyang ◽

Lijun Wang ◽

...

Keyword(s):

Epigenetic Regulation ◽

Chondrogenic Differentiation ◽

Transcriptional Control ◽

Bone Development ◽

Skeletal Development ◽

Hypoxia Inducible Factor ◽

Fracture Repair ◽

Skeletal Growth ◽

Long Bone ◽

Chondrocyte Differentiation

AbstractChondrocyte differentiation is a critical process for endochondral ossification, which is responsible for long bone development and fracture repair. Considerable progress has been made in understanding the transcriptional control of chondrocyte differentiation; however, epigenetic regulation of chondrocyte differentiation remains to be further studied. NSD1 is a H3K36 (histone H3 at lysine 36) methyltransferase. Here, we showed that mice with Nsd1 deficiency in Prx1+ mesenchymal progenitors but not in Col2+ chondrocytes showed impaired skeletal growth and fracture healing accompanied by decreased chondrogenic differentiation. Via combined RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we identified sex determining region Y box 9 (Sox9), the key transcription factor of chondrogenic differentiation, as a functional target gene of NSD1. Mechanistically, NSD1 regulates Sox9 expression by modulating H3K36me1 and H3K36me2 levels in the Sox9 promoter region, constituting a novel epigenetic regulatory mechanism of chondrogenesis. Moreover, we found that NSD1 can directly activate the expression of hypoxia-inducible factor 1α (HIF1α), which plays a vital role in chondrogenic differentiation through its regulation of Sox9 expression. Collectively, the results of our study reveal crucial roles of NSD1 in regulating chondrogenic differentiation, skeletal growth, and fracture repair and expand our understanding of the function of epigenetic regulation in chondrogenesis and skeletal biology.

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Pka, Ras and RGS Protein Interactions Regulate Activity of AflR, a Zn(II)2Cys6 Transcription Factor in Aspergillus nidulans

Genetics ◽

10.1093/genetics/165.3.1095 ◽

2003 ◽

Vol 165 (3) ◽

pp. 1095-1104

Author(s):

Kiminori Shimizu ◽

Julie K Hicks ◽

Tzu-Pi Huang ◽

Nancy P Keller

Keyword(s):

Transcription Factor ◽

Transcriptional Regulation ◽

Aspergillus Nidulans ◽

G Protein ◽

Protein Interactions ◽

Transcriptional Control ◽

G Protein Signaling ◽

Protein Signaling ◽

Rgs Protein ◽

Post Transcriptional Regulation

Abstract Sterigmatocystin (ST) is a carcinogenic polyketide produced by several filamentous fungi including Aspergillus nidulans. Expression of ST biosynthetic genes (stc genes) requires activity of a Zn(II)2Cys6 transcription factor, AflR. aflR is transcriptionally and post-transcriptionally regulated by a G-protein/cAMP/protein kinase A (PkaA) signaling pathway involving FlbA, an RGS (regulator of G-protein signaling) protein. Prior genetic data showed that FlbA transcriptional regulation of aflR was PkaA dependent. Here we show that mutation of three PkaA phosphorylation sites in AflR allows resumption of stc expression in an overexpression pkaA background but does not remediate stc expression in a ΔflbA background. This demonstrates negative regulation of AflR activity by phosphorylation and shows that FlbA post-transcriptional regulation of aflR is PkaA independent. AflR nucleocytoplasmic location further supports PkaA-independent regulation of AflR by FlbA. GFP-tagged AflR is localized to the cytoplasm when pkaA is overexpressed but nuclearly located in a ΔflbA background. aflR is also transcriptionally and post-transcriptionally regulated by RasA. RasA transcriptional control of aflR is PkaA independent but RasA post-transcriptional control of AflR is partially mediated by PkaA.

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TAZ is required for chondrogenesis and skeletal development

Cell Discovery ◽

10.1038/s41421-021-00254-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yang Li ◽

Shuting Yang ◽

Ling Qin ◽

Shuying Yang

Keyword(s):

Fracture Healing ◽

Bone Repair ◽

Bone Development ◽

Skeletal Development ◽

Ectopic Expression ◽

Bone Diseases ◽

Marker Genes ◽

Binding Motif ◽

Chondrocyte Maturation ◽

Proliferation And Differentiation

AbstractChondrogenesis is a major contributor to skeletal development and maintenance, as well as bone repair. Transcriptional coactivator with PDZ-binding motif (TAZ) is a key regulator of osteogenesis and adipogenesis, but how TAZ regulates chondrogenesis and skeletal development remains undefined. Here, we found that TAZ expression is gradually increased during chondrogenic differentiation. Deletion of TAZ in chondrocyte lineage impaired articular and growth plate, as well as the bone development in TAZ-deficient mice. Consistently, loss of TAZ impaired fracture healing. Mechanistically, we found that ectopic expression of TAZ markedly promoted chondroprogenitor proliferation, while deletion of TAZ impaired chondrocyte proliferation and differentiation. TAZ associated with Sox5 to regulate the expression and stability of Sox5 and downstream chondrocyte marker genes’ expression. In addition, overexpression of TAZ enhanced Col10a1 expression and promoted chondrocyte maturation, which was blocked by deletion of TAZ. Overall, our findings demonstrated that TAZ is required for skeletal development and joint maintenance that provided new insights into therapeutic strategies for fracture healing, heterotopic ossification, osteoarthritis, and other bone diseases.

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Early Induction ofCDKN1A(p21) andGADD45mRNA by a Low Dose of Ionizing Radiation is due to Their Dose-Dependent Post-transcriptional Regulation

Radiation Research ◽

10.1667/0033-7587(2002)157[0478:eiocpa]2.0.co;2 ◽

2002 ◽

Vol 157 (4) ◽

pp. 478-482 ◽

Cited By ~ 27

Author(s):

Kazuhiro Daino ◽

Sachiko Ichimura ◽

Mitsuru Nenoi

Keyword(s):

Transcriptional Regulation ◽

Ionizing Radiation ◽

Low Dose ◽

Post Transcriptional Regulation ◽

Dose Dependent

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mRNA Metabolism in Cardiac Development and Disease: Life After Transcription

Physiological Reviews ◽

10.1152/physrev.00007.2019 ◽

2020 ◽

Vol 100 (2) ◽

pp. 673-694 ◽

Cited By ~ 1

Author(s):

Chen Gao ◽

Yibin Wang

Keyword(s):

Transcriptional Regulation ◽

Rna Processing ◽

Transcriptional Control ◽

Cardiac Development ◽

New Era ◽

Mrna Metabolism ◽

Transcript Processing ◽

Rna Maturation ◽

Post Transcriptional Regulation ◽

Made In

The central dogma of molecular biology illustrates the importance of mRNAs as critical mediators between genetic information encoded at the DNA level and proteomes/metabolomes that determine the diverse functional outcome at the cellular and organ levels. Although the total number of protein-producing (coding) genes in the mammalian genome is ~20,000, it is evident that the intricate processes of cardiac development and the highly regulated physiological regulation in the normal heart, as well as the complex manifestation of pathological remodeling in a diseased heart, would require a much higher degree of complexity at the transcriptome level and beyond. Indeed, in addition to an extensive regulatory scheme implemented at the level of transcription, the complexity of transcript processing following transcription is dramatically increased. RNA processing includes post-transcriptional modification, alternative splicing, editing and transportation, ribosomal loading, and degradation. While transcriptional control of cardiac genes has been a major focus of investigation in recent decades, a great deal of progress has recently been made in our understanding of how post-transcriptional regulation of mRNA contributes to transcriptome complexity. In this review, we highlight some of the key molecular processes and major players in RNA maturation and post-transcriptional regulation. In addition, we provide an update to the recent progress made in the discovery of RNA processing regulators implicated in cardiac development and disease. While post-transcriptional modulation is a complex and challenging problem to study, recent technological advancements are paving the way for a new era of exciting discoveries and potential clinical translation in the context of cardiac biology and heart disease.

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RNA Granules: A View from the RNA Perspective

Molecules ◽

10.3390/molecules25143130 ◽

2020 ◽

Vol 25 (14) ◽

pp. 3130 ◽

Cited By ~ 1

Author(s):

Siran Tian ◽

Harrison A. Curnutte ◽

Tatjana Trcek

Keyword(s):

Transcriptional Regulation ◽

Rna Structure ◽

Transcriptional Control ◽

Rna Binding ◽

Rna Binding Proteins ◽

Special Issue ◽

Rna Granules ◽

Rna Biology ◽

A Cell ◽

Post Transcriptional Regulation

RNA granules are ubiquitous. Composed of RNA-binding proteins and RNAs, they provide functional compartmentalization within cells. They are inextricably linked with RNA biology and as such are often referred to as the hubs for post-transcriptional regulation. Much of the attention has been given to the proteins that form these condensates and thus many fundamental questions about the biology of RNA granules remain poorly understood: How and which RNAs enrich in RNA granules, how are transcripts regulated in them, and how do granule-enriched mRNAs shape the biology of a cell? In this review, we discuss the imaging, genetic, and biochemical data, which have revealed that some aspects of the RNA biology within granules are carried out by the RNA itself rather than the granule proteins. Interestingly, the RNA structure has emerged as an important feature in the post-transcriptional control of granule transcripts. This review is part of the Special Issue in the Frontiers in RNA structure in the journal Molecules.

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