Posttranscriptional Regulation

This contradistinct posttranscriptional regulation results though impaired interactions with an RNA binding protein MBNL1 that binds to expanded repeats.

From: Progress in Genomic Medicine , 2022

Maternal Consequence Genes in Development

Theresa Gross-Thebing , Erez Raz , in Current Topics in Developmental Biology, 2020

Abstract

Posttranscriptional regulation is a fundamental role of controlling gene expression in different jail cell types, in detail in the context of specification, maintenance and differentiation of germline cells. A fundamental regulator of these processes is the vertebrate poly peptide Dead end (Dnd). This RNA-bounden poly peptide is important for the survival and preservation of the fate of primordial germ cells (PGCs) and for subsequent development of the male germline. In this chapter, nosotros review the biological and molecular functions of the poly peptide and propose a model that takes into account the diverse roles described for Dnd in the germline. According to this model, Dnd functions as a scaffold that tin demark a wide range of RNA molecules and, at the same time, provides a platform for a diversity of proteins that touch on posttranscriptional processes such equally RNA stability and translation. This scenario offers a mechanistic ground for the control of diverse molecular processes in different contexts in germline development past the Dnd protein.

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Nitric Oxide

Zhong Guo , David A. Geller , in Vitamins & Hormones, 2014

4 Decision

Transcriptional and posttranscriptional regulations are ii major mechanisms for hiNOS cistron regulation. Pathways in human iNOS expression vary in different cells and tissues. Transcription factors such every bit NF-κB, AP one, and STAT-1α functionally binding to their respective elements in hiNOS promoter are necessary for human being iNOS transcription in most human cells. However, a quite complex network of RNA-BP (AUF1, HuR, KSRP, PTB, TIAR, TTP, and PABP) is involved in the posttranscriptional regulation of human iNOS expression. Moreover, recent data also indicates that regulation of homo iNOS expression is also controlled by miRNAs such as miR-939, miR-146a, and miR-26a.

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Chemical and Synthetic Biology Approaches To Empathize Cellular Functions - Part A

Simone Rauch , Bryan C. Dickinson , in Methods in Enzymology, 2019

Abstract

Posttranscriptional regulation of RNA has emerged every bit an important regulator of genetic information period in eukaryotic systems. In particular, chemical modifications of RNA have recently been established every bit cardinal regulatory marks that touch the lifetime, location, trafficking, and function of messenger RNA (mRNA). In mammalian systems, Due north half-dozen -methyladenosine (gsixA) is the almost prevalent mRNA modification, and the writer, eraser, and reader proteins that install, remove, or recognize msixA have been chop-chop uncovered and studied at the whole cell level. Understanding the furnishings of specific m6A modifications and their regulation at the single transcript level is the fundamental next footstep to understanding the mechanism and consequences of epitranscriptomic regulation. We recently adult programmable m6A reader proteins to study the effects of epitranscriptomic regulatory factors at private RNA transcripts. In this chapter, we hash out the awarding of targeted chiliadhalf-dozenA readers to study RNA regulation at single endogenous sites. We briefly introduce what is currently known nigh the Due north half dozen -methyltranscriptome and the Cas13 RNA-targeting family of proteins before detailing our protocol to study RNA modifications with targeted reader proteins.

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International Review of Cell and Molecular Biology

T. Tran , ... A.D. Pyle , in International Review of Cell and Molecular Biology, 2013

4.2 miRNAs Regulate Myogenesis

Posttranscriptional regulation during myogenesis has been more recently examined in the context of microRNAs (miRNAs). miRNAs are noncoding RNAs of approximately 22 nucleotides in length that negatively regulate by targeting mRNA ( Bartel, 2004). miR-i, miR-133, and miR-206 are the most widely studied miRNAs. Thus far, miR-206 is known to be specific to only skeletal muscle, whereas miR-1 is present in both skeletal and cardiac muscles, and miR-133 is nowadays in skeletal, cardiac, and smooth muscles (Williams et al., 2009). miR-1 and miR-206 promote myoblast differentiation, whereas miR-133 promotes myoblast proliferation (Chen et al., 2006; Kim et al., 2006). miR-one and miR-133 share common activators in the transcription factors serum response factor (SRF), MyoD and Mef2 (Liu et al., 2007; Zhao et al., 2005).

The abundant variety and sequence specificity of miRNAs let for tight regulation of myogenesis. miRNA regulation is withal another potentially powerful tool not only to aid deconstruct and understand the regulatory network of myogenesis, just it may also one twenty-four hours serve therapeutic purposes for muscular diseases.

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Regulation of Gut Barrier Function past RNA-Binding Proteins and Noncoding RNAs

Hee Kyoung Chung , ... Jian-Ying Wang , in Reference Module in Biomedical Sciences, 2021

6 Conclusions and time to come perspectives

Posttranscriptional regulation of gene expression, particularly contradistinct mRNA stability and translation in the intestinal epithelium by RBPs and ncRNAs, represents an important layer of complication governing the gut bulwark office in response to stressful environments. RBPs and ncRNAs and their interactions each other and with mRNAs have a vast spectrum of functions in physiology and pathology of the intestinal epithelium, although virtually circRNAs in the gut mucosa have not been identified and fully investigated yet. The results summarized hither provide evidence that several RBPs and ncRNAs including miRNAs and lncRNAs expressed highly in the intestinal epithelium participate in a wide variety of biological processes and play an essential role in the regulation of gut bulwark function under diverse pathophysiological weather condition. Amidst RBPs, HuR plays a pivotal part in sustaining integrity and effectiveness of the intestinal barrier function through several mechanisms. HuR stabilizes and/or promotes translation of mRNAs encoding TJs and barrier-promoting/protecting factors, thus increasing their expression and enhancing the barrier function. Target deletion of HuR in mice results in the barrier dysfunction by inhibiting TJ expression, impairing the epithelial renewal, delaying mucosal repair subsequently acute injury, and compromising the epithelium-host defense. On the other paw, CUGBP1, AUF1, and TIAR destabilize and/or inhibit translation of these mRNAs, thereby downregulating the barrier function. The intestinal barrier function is too tightly regulated by ii groups of ncRNAs: the negative ncRNAs, including miR-29b, miR-195, miR-222, miR-675, and lncRNA H19, and positive ncRNAs such as miR-503/322 and lncRNAs such equally SPRY4-IT1, uc.173, and Gata6. HuR and CUGBP1 can collaborate with both negative and positive ncRNAs and regulate their bounden and biological functions either synergistically or antagonistically. Normal gut barrier part depends on a dynamic remainder betwixt the deportment of diverse RBPs and ncRNAs and their interactions with mRNAs and/or other regulatory factors.

Looking forward, there are still many gaps in our knowledge well-nigh RBPs and ncRNAs in pathophysiology of the intestinal epithelium and their potential therapeutic application. RBPs and ncRNAs are likely to continue to better enable researchers to define the verbal mechanisms underlying control of the gut barrier function and find molecular signatures that help to early diagnose the gut bulwark dysfunction in patients with critical disorders. The exact processes decision-making the expression levels of these functional RBPs and ncRNAs in the intestinal epithelium remain largely unknown. Current efforts utilise country-of-the-art techniques to image ncRNAs at high resolution in vivo and to identify ncRNAs using loftier-throughput technologies. Intestinal epithelial tissue-specific genetic mouse models will provide important information on the in vivo functions of specific RBPs and ncRNAs in response to unlike stresses and pathologies. Translation of this wealth of cognition of RBPs and ncRNAs to therapeutics is also a challenging task. Although studies using human mucosal tissue samples from patients with gut bulwark dysfunction are limited and so far, they are necessary to establish the important touch of contradistinct RBPs and ncRNAs on disease pathogenesis and devise therapeutic venues. With the rapid accelerate of RNA biology and more in-depth studies that are to fully define the molecular insights how RBPs and ncRNAs control the gut barrier role and epithelium homeostasis, drugs based on RBPs and/or ncRNAs involved in gut barrier pathways will 1 day be available to preserve the gut bulwark integrity for patients with disquisitional disorders.

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Ferritin☆

J.J. Winzerling , D.Q.D. Pham , in Reference Module in Life Sciences, 2017

four.2 Post-Transcriptional Control: Alternative Splicing and Polyadenylation

Post-transcriptional control of ferritin synthesis also occurs in insects (Canonne-Hergaux et al., 2001; Zhang et al., 2001a), and includes culling splicing (Lind et al., 1998; Georgieva et al., 1999), use of multiple polyadenylation sites (Lind et al., 1998; Georgieva et al., 1999, 2002a,b; Dunkov et al., 2002) and translational repression by an atomic number 26 responsive chemical element (IRE; Zhang et al., 2001a, 2002).

In mammals, the IRE is a cis-acting, stem loop sequence that allows atomic number 26-mediated repression of ferritin translation (Leibold and Munro, 1988; Theil, 1994). A single IRE is found in the 5′-untranslated region (UTR) of mammalian ferritin mRNA (Caughman et al., 1988). An IRE also is present in the 5′-UTR of the mRNA for the ferritin HCH and LCH for several insects (Tables 1 and 2).

In dissimilarity to these ferritin messages, the LCH message of the dipterans, Drosophila (Georgieva et al., 2002a,b) and Aedes (Pham et al., 2005) lacks a canonical IRE. Although not seen in mammals, ferritin subunits without IREs are found in other organisms (Dietzel et al., 1992). The LCH message in both dipterans is increased in response to iron. All the same, the protein does non appear to increase in proportion to bulletin upwardly-regulation – suggesting, maybe, that in improver to transcriptional control, other mechanisms control synthesis of these subunits. This is supported past the finding that the Drosophila LCH is encoded past ii mRNA that differ in length as a result of using alternative polyadenylation sites (Georgieva et al., 2002a,b). Iron loading significantly increases the shorter message and induces both transcripts in all life stages, except night pupae. Vertebrate ferritin mRNA levels can be increased through bounden of proteins to conserved polypyrimidine regions in the 3′ UTR that increment ferritin mRNA stability (Ai and Chau, 1999). Whether this is the case for these letters in this insect is unknown.

In contrast to the Drosophila LCH message, the Drosophila HCH message has a canonical IRE (Charlesworth et al., 1997) that could be removed by alternative splicing (Lind et al., 1998; Georgieva et al., 1999). In fact, 8 letters for the ferritin HCH exist in Drosophila that originate from three alternative splicing sites coupled with either of two polyadenylation sites (Lind et al., 1998). In all cases, alternative splicing removes the IRE. Atomic number 26 treatment increases splicing activity in a tissue specific fashion with the greatest increase in spliced message occurring in the gut (Georgieva et al., 1999). When a high level of HCH is desirable for rapid storage of iron, culling splicing of the IRE could permit unhindered expression of this subunit.

In contrast to the Drosophila HCH bulletin, no culling splicing is seen for the Aedes HCH message (Dunkov et al., 2002). Two messages for Aedes HCH have been identified, but they occur as a consequence of using different polyadenylation sites. Both messages increment in females following iron supplementation or blood feeding (Dunkov et al., 2002). The longer message increases progressively later on blood feeding and is sustained for 7 days. While the shorter bulletin increases progressively, exceeds the level of the longer bulletin at 48 h, and then declines. Both letters are present in ovaries, midgut, and thorax – with greatest expression in midgut. Only the larger message is observed in malpighian tubules and fat body.

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miRNA and Cancer

Catia Moutinho , Manel Esteller , in Advances in Cancer Research, 2017

4.two Transcriptional Epigenetic Modulation by miRNAs

Besides mRNA posttranscriptional regulation in the cytoplasm, unlike studies demonstrated that endogenous miRNAs tin can directly affect gene expression in the nucleus at the transcriptional level. For instance, as shown in Fig. iiB miR-320, is encoded within the promoter region of the POLR3D gene in the antisense orientation. The mature miRNA tin direct the recruitment of AGO1 proteins and the PRC2 component EZH2 at the POLR3D promoter, resulting in H3K27 trimethylation and transcriptional silencing of POLR3D (Kim, Saetrom, Snove, & Rossi, 2008). Another example is miR-423-5p that tin can recognize target sites at the PR promoter and participates in the recruitment of AGO2 to a noncoding transcript that overlaps the promoter region. This suggests that the recognition of nascent noncoding RNA transcripts serves as a mechanism that miRNAs apply for transcriptional factor silencing (Younger & Corey, 2011).

Finally, an additional example corroborates that miRNAs can as well induce promoter activation as well as repression. The cyclin B1 (CCNB1) promoter contains highly complementary sites for 21 miRNAs. Among them, miR-744, miR-1186, and miR-466d-3p can induce CCNB1 expression. Conversely, knockdown of endogenous miR-744 leads to decreased CCNB1 levels. miR-744 favors the recruitment of AGO1 and RNA POL II to the CCNB1 promoter, and results in H3K4 trimethylation activating chromatin marker at the CCNB1 transcription outset site (Huang et al., 2012). Thus, endogenous miRNAs can either induce or repress the expression of specific genes by recognizing specific target sites at the promoter regions.

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Volume 2

Shubha Priyamvada , ... Pradeep K. Dudeja , in Physiology of the Gastrointestinal Tract (6th Edition), 2018

57.2.three.2.ii Posttranscriptional Regulation

MCT1 is likewise nether posttranscriptional regulation by microRNAs. The MCT1 untranslated region is a target for three microRNAs (miR-29a, miR-29b, and miR-124) and miR-29a and miR-29b have been reported to silence MCT1 mRNA expression in mouse pancreatic β cells. 359 However, in colonic epithelial cells, miR-29a, b, and c decreased MCT1 poly peptide expression only did not alter MCT1 mRNA levels. 360 Posttranscriptional regulation of MCT1 could also involve regulation of its translation. Such translational command of protein synthesis usually involves specific sequences and secondary structure in the 5′ or frequently, 3′-untranslated region (UTR). Initiation factors such as eIF4E and other regulatory factors such every bit Maskin or Cup are thought to interact with these regions to enhance or repress translation. 350,361 Posttranscriptional upregulation of MCT1 expression increased several fold during the postmitotic and G1 phases of the cell cycle in the absenteeism of a change in MCT1 mRNA. Importantly, the 3′-UTR of MCT1 contains a potential cytosolic polyadenylation element and hexanucleotide elements thought to be disquisitional in the regulation of polyadenylation at the exit from the mitotic phase in the cell bike that in turn may save Maskin or Loving cup inhibition of eIF4E. 361 Also, the phosphorylation states of eIF4E and 4EBP1 modify during the prison cell cycle in parallel with changes in the translation and information technology has been shown that the time of maximal 4E-BP1 phosphorylation corresponds with the summit of MCT1 expression in HeLa cells. 362 It is possible that these initiation factors may exist of relevance in regulating MCT1 expression and SCFA assimilation in the intestine; even so, this nevertheless remains to be investigated.

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Dendrite Development

W.B. Grueber , in Cellular Migration and Formation of Neuronal Connections, 2013

10.6.2 miRNAs in Dendritic Evolution

A critical pathway for posttranscriptional regulation of cistron expression is via miRNA-mediated translational repression. Mature miRNAs are generated past successive enzymatic steps involving the generation of pre-miRNAs by Drosha, an RNase Iii, and Pasha, a double-stranded RNA (dsRNA)-binding poly peptide. Dicer, another RNase III and then cleaves the pre-miRNAs to generate mature miRNAs.

Roles for miRNAs in dendritic development are, at present, poorly understood. Nonetheless, a few results advise potentially important roles for this type of gene regulation. Both pasha and dicer were identified in a forwards genetic screen for mutations that affect olfactory PN dendritic targeting (Berdnik et al., 2008). Specific subsets of PNs showed cell democratic defects in both dendritic targeting and axon morphology in higher brain centers upon knockdown of either of these two components. Dendrites of all PNs are not as affected, but those that are show poor innervation of their normal glomerulus too as ectopic innervation of additional glomeruli. These results implicate the miRNA processing pathway in dendritic targeting, but leave open up the identity of specific miRNA(due south) that mediate PN targeting. Additionally, in Drosophila da neurons, increased levels of the pre-miRNA, pre-miR124a strongly suppresses dendritic branching (Xu et al., 2008). The normal function for miR124 for dendritic development, and whether this could be 1 of the miRNAs responsible for the dicer and pasha mutant phenotypes in PNs, is not clear. Finally, as volition be discussed beneath, the runted miRNA has a nonautonomous part in the control of dendritic elaboration in Drosophila sensory neurons (Parrish et al., 2009).

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Vitamin D and the Parathyroids

Justin Argent , Tally Naveh-Many , in Vitamin D (Fourth Edition), 2018

microRNAs in the Parathyroid

Parathyroid-Specific Deletion of Dicer-Dependent microRNAs Abrogates the Response of the Parathyroid to Acute and Chronic Hypocalcemia and Uremia

A further level of posttranscriptional regulation of PTH gene expression is by microRNAs (miRNAs). miRNAs downregulate cistron expression and accept vital roles in biology just their functions in the parathyroid were unexplored. The terminal stride in miRNA maturation is cleavage by dicer protein in the cytoplasm [103]. We generated parathyroid-specific Dicer1 knockout (PT-Dicer −/− ) mice where parathyroid miRNA maturation is blocked only in the parathyroid [10]. Despite normal basal PTH, under atmospheric condition of stress, deletion of dicer and the subsequent absence of mature miRNAs in the mouse parathyroid had surprising effects on parathyroid function. Remarkably, the PT-Dicer −/− mice did not increase serum PTH in response to acute hypocalcemia compared with the >fivefold increase in controls (Fig. 27.three). PT-Dicer −/− glands cultured in low-calcium medium secreted fivefold less PTH at 1.5   h than controls (Fig. 27.4). Chronic hypocalcemia increased serum PTH >fourfold less in PT-Dicer −/− mice compared with control mice with no increment in PTH mRNA levels and parathyroid cell proliferation compared to the 2- to 3-fold increase in hypocalcemic controls [ten]. The importance of our findings is underlined past the fact that uremic PT-Dicer −/− mice with normal serum calcium had an impaired increment in serum PTH like to their failure to answer to hypocalcemia. Therefore, parathyroid miRNAs are necessary for the evolution of SHP not only of chronic hypocalcemia merely also of uremia (Fig. 27.4). In chronic hypocalcemia there are loftier levels of i,25(OH)2Diii, whilst in uremia at that place are depression levels of 1,25(OH)2D3 suggesting that in these chronic models the effect of miRNA depletion is not due to changes in vitamin D. In dissimilarity to the impaired increase in PTH by hypocalcemia and uremia, the PT-Dicer −/− mice decreased serum PTH as expected subsequently activation of the parathyroid Automobile by both hypercalcemia and a calcimimetic, demonstrating that they are dicer-independent. In decision, miRNAs are essential for activation of the parathyroid by both acute and chronic hypocalcemia and uremia, the major stimuli for PTH secretion (Fig. 27.iv) [10,11].

Figure 27.3. miRNAs are essential for the activation of the parathyroid past hypocalcemia and uremia. (A) Parathyroid hormone (PTH)–calcium human relationship before and later ethylene glycol tetraacetic acid administration in parathyroid-specific dicer knockout mice (PT-Dicer −/− ) and control mice. The PT-Dicer −/− mice did non increase their serum PTH after astute hypocalcemia different command mice. (B) Individual thyroparathyroid explants from command and PT-Dicer −/− mice were cultured in standard or calcium-depleted medium. The parathyroid glands from the PT-Dicer −/− mice secreted less PTH than glands from control mice.

 Reproduced from Shilo V, Silver J, Naveh-Many T. Micro-RNAs in the parathyroid: a new portal in understanding secondary hyperparathyroidism. Curr Opin Nephrol Hypertens 2016;25.

Figure 27.four. Model for the part of microRNAs (miRNAs) in stimulation of the parathyroid past hypocalcemia and uremia. Parathyroid miRNAs are essential for the increase in parathyroid gland activity by acute and chronic hypocalcemia and uremia, mediating the increase in parathyroid hormone (PTH) messenger RNA (mRNA) levels, PTH secretion, and parathyroid cell proliferation. Suppression of parathyroid action past hypercalcemia or a calcimimetic is miRNA independent. CKD, chronic kidney illness.

 Reproduced from Shilo V, Silver J, Naveh-Many T. Micro-RNAs in the parathyroid: a new portal in understanding secondary hyperparathyroidism. Curr Opin Nephrol Hypertens 2016;25.

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