Current Genomics (v.10, #3)

The recent explosion of research on the role of noncoding RNAs (ncRNA) in the control of gene expression has revealed multifaceted implications concerning the regulation of numerous mammalian systems, ranging from determination of cell fate during development to maintenance of terminally differentiated states. Among the various types of ncRNA, microRNAs are probably the best known group; their functional impact in signaling pathways controls normal processes regulating apoptosis, cell cycle traverse, differentiation, cytoskeletal organization, etc. at the post-transcriptional level, by either degrading their target genes' messages through binding at the coding region, or inhibiting translation at the 3'-untranslated region. Not surprisingly, dysregulation of microRNA expression has been linked to the pathogenesis of a variety of diseases, among which cancer, cardiovascular disorders, and neurodegeneration have proven fertile grounds for investigation. This issue focuses on a discussion of microRNA's post-transcriptional control of the aging process. The paper by Ibanez- Ventoso and Driscoll provides a comprehensive review of the potential impact of microRNA expression on health span, based upon the well-known aging model, C. elegans, with the latest miRbase 10.1 version stating that 73 out of 139 worm miRNAs have sequence relationship to known human miRNAs. Understanding how they control the signaling networks that modulate aging in the worm should provide major insights into the aging process of mammalian species, including man. Notwithstanding the essential role of microRNA in cancer etiology, the biggest impact of microRNA regulation of post-transcriptional control of gene expression may be that associated with neurodegeneration. The paper by Maes, et al. reviews the basic knowledge of how microRNAs control neuronal cell fate during development, and includes recent evidence that changes in expression levels of this noncoding RNA species are vital to the pathogenesis of a wide variety of disorders associated with the central nervous system, as well as being systemically manifested in peripheral blood mononuclear cells. Of all the complex hormonal control mechanisms of the mammalian aging process, estrogen is perhaps the most significant single factor, since many of the disorders seen in the female aging population are attributed to the functional decline associated with menopause. In this context, the paper by Klinge describes aberrant patterns of microRNA expression in assorted estrogen-related cancers, the most notorious being breast cancer; the role of estrogen-regulated changes in expression of microRNAs and their downstream target genes in the aging process are discussed. Beyond the recognition of microRNAs as a vital molecular species for repression of gene expression at the post-transcriptional level, increasing reports indicate that their transcriptional regulation is equally important, and follows the well-established mechanisms of promoter-dependent regulation with coordinated genomic organization in terms of transcriptional start sites, cis elements, activation by transcriptional factors, etc. Along this line, Liang, et al. reviews the genomic structures and organization of microRNA genes, and how changes such as oxidative stress during aging can affect the transcriptional regulation of microRNA expression. Among all the transcriptional factors affecting microRNA expression, p53 may be the best known, since its multiple functions are implicated in cancer, senescence, and apoptosis. In the paper by Takwi and Li, the p53-directed pathway is reviewed in detail, specifically how it activates microRNAs which affect genes involved in various components of this noted signaling network. In conclusion, this issue provides, for the first time, a collection of papers describing the importance of microRNAs in controlling the aging process, and their possible roles in the etiology of age-dependent diseases. We hope this compendium will stimulate further research in this area, a fertile ground for study of the post-transcriptional control of gene expression during the aging process.

MicroRNAs in C. elegans Aging: Molecular Insurance for Robustness? by Carolina Ibanez-Ventoso, Monica Driscoll (144-153).
The last decade has witnessed a revolution in our appreciation of the extensive regulatory gene expression networks modulated by small untranslated RNAs. microRNAs (miRNAs), and#x223C;22 nt RNAs that bind imperfectly to partially homologous sites on target mRNAs to regulate transcript expression, are now known to influence a broad range of biological processes germane to development, homeostatic regulation and disease. It has been proposed that miRNAs ensure biological robustness, and aging has been described as a progressive loss of system and cellular robustness, but relatively little work to date has addressed roles of miRNAs in longevity and healthspan (the period of youthful vigor and disease resistance that precedes debilitating decline in basic functions). The C. elegans model is highly suitable for testing hypotheses regarding miRNA impact on aging biology: the lifespan of the animal is approximately three weeks, there exist a wealth of genetic mutations that alter lifespan through characterized pathways, biomarkers that report strong healthspan have been defined, and many miRNA genes have been identified, expression-profiled, and knocked out. 50/114 C. elegans miRNAs change in abundance during adult life, suggesting significant potential to modulate healthspan and lifespan. Indeed, miRNA lin-4 has been elegantly shown to influence lifespan and healthspan via its lin-14 mRNA target and the insulin signaling pathway. 27 of the C. elegans age-regulated miRNAs have sequence similarity with both fly and human miRNAs. We review current understanding of a field poised to reveal major insights into potentially conserved miRNA-regulated networks that modulate aging.

MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders by Olivier Maes, Howard Chertkow, Eugenia Wang, Hyman Schipper (154-168).
Understanding complex diseases such as sporadic Alzheimer disease (AD) has been a major challenge. Unlike the familial forms of AD, the genetic and environmental risks factors identified for sporadic AD are extensive. MicroRNAs are one of the major noncoding RNAs that function as negative regulators to silence or suppress gene expression via translational inhibition or message degradation. Their discovery has evoked great excitement in biomedical research for their promise as potential disease biomarkers and therapeutic targets. Key microRNAs have been identified as essential for a variety of cellular events including cell lineage determination, proliferation, apoptosis, DNA repair, and cytoskeletal organization; most, if not all, acting to fine-tune gene expression at the post-transcriptional level in a host of cellular signaling networks. Dysfunctional microRNA-mediated regulation has been implicated in the pathogenesis of many disease states. Here, the current understanding of the role of miRNAs in the central nervous system is reviewed with emphasis on their impact on the etiopathogenesis of sporadic AD.

Estrogen Regulation of MicroRNA Expression by Carolyn Klinge (169-183).
Women outlive men, but life expectancy is not influenced by hormone replacement (estrogen + progestin) therapy. Estrogens appear to protect brain, cardiovascular tissues, and bone from aging. Estrogens regulate genes directly through binding to estrogen receptors alpha and beta (ERand#945; and ERand#946;) that are ligand-activated transcription factors and indirectly by activating plasma membrane-associated ER which, in turns, activates intracellular signaling cascades leading to altered gene expression. MicroRNAs (miRNAs) are short (19-25 nucleotides), naturally-occurring, non-coding RNA molecules that base-pair with the 3' untranslated region of target mRNAs. This interaction either blocks translation of the mRNA or targets the mRNA transcript to be degraded. The human genome contains and#x223C; 700-1,200 miRNAs. Aberrant patterns of miRNA expression are implicated in human diseases including breast cancer. Recent studies have identified miRNAs regulated by estrogens in human breast cancer cells, human endometrial stromal and myometrial smooth muscle cells, rat mammary gland, and mouse uterus. The decline of estradiol levels in postmenopausal women has been implicated in various age-associated disorders. The role of estrogen-regulated miRNA expression, the target genes of these miRNAs, and the role of miRNAs in aging has yet to be explored.

Epigenetic Control of MicroRNA Expression and Aging by Ruqiang Liang, David Bates, Eugenia Wang (184-193).
MicroRNAs are a major category among the noncoding RNA fraction that negatively regulate gene expression at the post-transcriptional level, by either degrading the target messages or inhibiting their translation. MicroRNAs may be referred to as and#x2018;dimmer switchesand#x2019; of gene expression, because of their ability to repress gene expression without completely silencing it. Whether through up-regulating specific groups of microRNAs to suppress unwanted gene expressions, or by down-regulating other microRNAs whose target genes' expression is necessary for cellular function, such as cell proliferation, apoptosis, or differentiation, these regulatory RNAs play pivotal roles in a wide variety of cellular processes. The equilibrium between these two groups of microRNA expressions largely determines the function of particular cell types. Our recent results with several model systems show that upon aging, there is a trend of up-regulation of microRNA expression, with concomitant inverse down-regulation of target genes. This review addresses molecular mechanisms that may provide the underlying control for this up-regulating trend, focusing on activation by various microRNAs' own promoters, through binding with pivotal transcription factors, stress response, methylation of clustered DNA domains, etc. Thus, epigenomic control of aging may be due in part to heightened promoter activation of unwanted microRNA expressions, which in turn down-regulate their target gene products. Overriding and dampening the activation of these noncoding RNAs may prove to be a new frontier for future research, to delay aging and extend healthy life-span.

The p53 Pathway Encounters the MicroRNA World by Apana Takwi, Yong Li (194-197).
The p53 protein is a transcription factor that regulates multiple cellular processes in human and other high eukaryotes including cell proliferation, differentiation, cell cycle, and metabolism. The central roles played by p53 in tumor development have drawn extensive studies on p53 activation and inactivation. The regulation of p53 and its pathway, as well as its transactivational targets is of prime importance in the understanding of tumorigenesis. Recently, microRNAs (miRNAs) have been reported to be directly transactivated by p53. Equally, p53 and components of its pathway have been shown to be targeted by miRNA thereby affecting p53 activities. In this review, we focus our discussion on the biological and pathological roles of miRNAs in the p53 pathway.

Cells grow in response to nutrients or growth factors, whose presence is detected and communicated by elaborate signaling pathways. Protein kinases play crucial roles in processes such as cell cycle progression and gene expression, and misregulation of such pathways has been correlated with various diseased states. Signals intended to promote cell growth converge on ribosome biogenesis, as the ability to produce cellular proteins is intimately tied to cell growth. Part of the response to growth signals is therefore the coordinate expression of genes encoding ribosomal RNA (rRNA) and ribosomal proteins (RP). A key player in regulating cell growth is the Target of Rapamycin (TOR) kinase, one of the gatekeepers that prevent cell cycle progression from G1 to S under conditions of nutritional stress. TOR is structurally and functionally conserved in all eukaryotes. Under favorable growth conditions, TOR is active and cells maintain a robust rate of ribosome biogenesis, translation initiation and nutrient import. Under stress conditions, TOR signaling is suppressed, leading to cell cycle arrest, while the failure of TOR to respond appropriately to environmental or nutritional signals leads to uncontrolled cell growth. Emerging evidence from Saccharomyces cerevisiae indicates that High Mobility Group (HMGB) proteins, non-sequence-specific chromosomal proteins, participate in mediating responses to growth signals. As HMGB proteins are distinguished by their ability to alter DNA topology, they frequently function in the assembly of higher-order nucleoprotein complexes. We review here recent evidence, which suggests that HMGB proteins may function to coordinate TOR-dependent regulation of rRNA and RP gene expression.

The molecular machines that replicate the genome consist of many interacting components. Essential to the organization of the replication machinery are ring-shaped proteins, like PCNA (Proliferating Cell Nuclear Antigen) or the and#946;- clamp, collectively named sliding clamps. They encircle the DNA molecule and slide on it freely and bidirectionally. Sliding clamps are typically associated to DNA polymerases and provide these enzymes with the processivity required to synthesize large chromosomes. Additionally, they interact with a large array of proteins that perform enzymatic reactions on DNA, targeting and orchestrating their functions. In recent years there have been a large number of studies that have analyzed the structural details of how sliding clamps interact with their ligands. However, much remains to be learned in relation to how these interactions are regulated to occur coordinately and sequentially. Since sliding clamps participate in reactions in which many different enzymes bind and then release from the clamp in an orchestrated way, it is critical to analyze how these changes in affinity take place. In this review I focus the attention on the mechanisms by which various types of enzymes interact with sliding clamps and what is known about the regulation of this binding. Especially I describe emerging paradigms on how enzymes switch places on sliding clamps during DNA replication and repair of prokaryotic and eukaryotic genomes.