• BRCA1
• DNA-damage response
• FMRP
• RNA-RNA interaction
• anti-cancer treatments
• circRNAs
• translational regulation

• Humans
• BRCA1 Protein/metabolism
• BRCA1 Protein/genetics
• RNA, Circular/metabolism
• RNA, Circular/genetics
• RNA, Messenger/metabolism
• RNA, Messenger/genetics
• DNA Damage
• Fragile X Mental Retardation Protein/metabolism
• Fragile X Mental Retardation Protein/genetics
• Protein Serine-Threonine Kinases/metabolism
• Protein Serine-Threonine Kinases/genetics
• Binding, Competitive
• Intracellular Signaling Peptides and Proteins/metabolism
• Intracellular Signaling Peptides and Proteins/genetics
• Gene Expression Regulation, Neoplastic
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• RNA/metabolism
• RNA/genetics
• HEK293 Cells
• Protein Binding
• Cell Line, Tumor
• Protein Biosynthesis
• MCF-7 Cells
• Female

• ASO
• LIN28
• Let-7
• mesenchymal stromal cells
• therapeutic potential

In vitro spermatogenesis appears to be a promising approach to restore the fertility of childhood cancer survivors. The rat model has proven to be challenging, since germ cell maturation is arrested in organotypic cultures. Here, we report that, despite a meiotic entry, abnormal synaptonemal complexes were found in spermatocytes, and in vitro matured rat prepubertal testicular tissues displayed an immature phenotype. RNA-sequencing analyses highlighted up to 600 differentially expressed genes between in vitro and in vivo conditions, including genes involved in blood-testis barrier (BTB) formation and steroidogenesis. BTB integrity, the expression of two steroidogenic enzymes, and androgen receptors were indeed altered in vitro. Moreover, most of the top 10 predicted upstream regulators of deregulated genes were involved in inflammatory processes or immune cell recruitment. However, none of the three anti-inflammatory molecules tested in this study promoted meiotic progression. By analysing for the first time in vitro matured rat prepubertal testicular tissues at the molecular level, we uncovered the deregulation of several genes and revealed that defective BTB function, altered steroidogenic pathway, and probably inflammation, could be at the origin of meiotic arrest.

• RNA-sequencing
• blood-testis barrier integrity
• in vitro spermatogenesis
• meiotic arrest
• rat prepubertal testis
• steroidogenesis

The ubiquitin-mediated degradation system is responsible for controlling various tumor-promoting processes, including DNA repair, cell cycle arrest, cell proliferation, apoptosis, angiogenesis, migration and invasion, metastasis, and drug resistance. The conjugation of ubiquitin to a target protein is mediated sequentially by the E1 (activating)‒E2 (conjugating)‒E3 (ligating) enzyme cascade. Thus, E2 enzymes act as the central players in the ubiquitination system, modulating various pathophysiological processes in the tumor microenvironment. In this review, we summarize the types and functions of E2s in various types of cancer and discuss the possibility of E2s as targets of anticancer therapeutic strategies.

• cancer
• ubiquitin-conjugating enzyme
• ubiquitination

Small, noncoding sequences of ribonucleic acid called microRNAs (miRNAs, miR) are functioning as posttranscriptional regulators of gene expression. As they draw increasing attention of rheumatologists, there is a growing body of evidence concerning specific molecules that may affect the long-term care of patients with inflammatory arthritides. Findings involving children with juvenile idiopathic arthritis (JIA) are still limited though. The aim of the study was to browse the available data on microRNAs which may be utilized as potential biomarkers helpful in diagnosing and monitoring JIA patients. The review contains a brief summary on the most studied sequences: miR-16, miR-125a-5p, miR-146a, miR-155, and miR-223. It is complemented with other miRNAs possibly relevant for JIA (miR-145, miR-23b, miR-27a, and miR-204) and discussion on challenges for using miRNAs in pediatric rheumatology (particularly, issues regarding specificity of biomarkers and measurements involving synovial fluid).

• Biomarker
• Extracellular vesicles
• Omics
• PD-Related genes
• Parkinson's disease
• α-synuclein

MicroRNAs (miRNAs) are considered to be strong prognostic markers and key therapeutic targets in human diseases, especially cancer. A sensitive monitoring platform for cancer-associated miRNA (oncomiR) action is needed for mechanistic studies, preclinical evaluation, and inhibitor screening. In this study, we developed and systemically applied a sensitive and efficient lentivirus-based system for monitoring oncomiR actions, essentially miR-21. The specificity and sensitivity of “miRDREL” against various oncomiRs were validated by checking for tight correlations between their expression and targeting efficacy. Experiments based on the transfection of synthetic mimics and antagomir-mediated depletion of oncomiRs further confirmed the specificity of the system. Systemic application of miRDRELs to natural oncomiR targets, knockdown of key microprocessors, and physiological triggering of oncomiRs also demonstrated that the system is an effective tool for monitoring cellular oncomiR action. Importantly, molecular modeling-based screening confirmed the action of the miR-21-targeting drug ivermectin and led to the identification of a new effective derivative, GW4064, for inhibiting oncogenic DDX23-miR-21 signaling. Furthermore, proteomic-kinase inhibitor screenings identified a novel oncogenic kinome-DDX23-miR-21 axis and thus expands our understanding of miR-21 targeting therapeutics in tumorigenesis. Taken together, these data indicate that miRDREL and its versatile application have great potential in basic, preclinical studies and drug development pipelines for miRNA-related diseases, especially cancer.

A new method for monitoring microRNAs (miRNAs), very short RNA molecules that regulate gene expression, shows promise for developing and testing new cancer therapies. These miRNAs are strongly implicated in cancer, and are used for diagnosis and as therapeutic targets. However, currently available systems for monitoring them are inefficient and lack capacity for scaling up. Jong Heon Kim and co-workers at the National Cancer Center in Goyang, South Korea, have developed a new miRNA monitoring method that can be used in multiple disease models, including long-term experiments in small animals. They used the method to clarify how the cancer drug ivermectin acts, to identify a molecule similar to ivermectin but that may be more effective, and to identify novel molecules that interact with cancer-related miRNAs. This method shows promise for both clinical and basic research applications.

The transformation in cells at genetic levels stimulatesthe proliferation of cancer. The current review highlights the role of miRNA in management of cancer by altering processes of body at cellular levels.

A deep research on the literature available till date for miRNA in cancer was conducted using various medical sites like PubMed, MEDLINE from internet and data was collected. The articles were majorly preferred in English language.

The development of normal cells into cancerous cells is a multivalent procedure highlighting numerous responsible factors. During the progression of cancer, the role of oncogene and tumor suppressor genes outshines at different levels of tumorogenesis. Metastasis poses highest threat in cancer progression and fabricates obstacles to clinicians and researchers in preventing formation of tumor on secondary sites. The mesenchymal-epithelial transition (MET) and epithelial mesenchymal transition (EMT) induce dissemination and ultimately progression of cancer.

A comprehensive knowledge of the altered genes and the mechanism by which they induce formation of tumor is essential as they contribute in proliferating cancer at various stages, aggravating clinical symptoms. Hence miRNAs can be efficiently employed as an emerging treatment therapy for cancer.

• Apoptosis
• Leukemia
• Metastasis
• Tumor suppressor genes
• carcinogenic

• CCR2
• CCR5
• CD4
• EAE
• IL-1R1
• IL-23R
• miRNA

• Animals
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/metabolism
• Cell Differentiation/immunology
• Cytokines/metabolism
• Disease Models, Animal
• Disease Susceptibility
• Encephalomyelitis, Autoimmune, Experimental
• Gene Expression Regulation
• Immunophenotyping
• Lymphocyte Activation/genetics
• Lymphocyte Activation/immunology
• Mice
• MicroRNAs/genetics
• Multiple Sclerosis/etiology
• Multiple Sclerosis/metabolism
• Multiple Sclerosis/pathology
• RNA Interference
• Th17 Cells/cytology
• Th17 Cells/immunology
• Th17 Cells/metabolism

• R01 AI146188 NIAID NIH HHS
• R21 AI133041 NIAID NIH HHS

This study aimed to explore the correlation of circulating microRNA (miRNA) expression profile with clinical response to tumor necrosis factor (TNF) inhibitor in treating rheumatoid arthritis (RA) patients.

Baseline PBMC samples from eight responders and eight non‐responders after 24‐week TNF inhibitor (etanercept) treatment were subjected to miRNA microarray. Then, top 10 dysregulated miRNAs were selected and further validated by quantitative polymerase chain reaction (qPCR) in baseline PBMC samples from 92 RA patients treated with 24‐week TNF inhibitor (etanercept). Responders and non‐responders were divided referring to the decline in disease activity score in 28 joints.

In microarray assay, total 59 upregulated and 78 downregulated miRNAs were identified in responders compared to non‐responders, which were mainly enriched in regulating immune‐ and inflammation‐related biological processes and pathways. The top 10 dysregulated miRNAs were as follows: miR‐192‐5p, miR‐146a‐5p, miR‐19b‐3p, miR‐320c, miR‐335‐5p, miR‐149‐3p, miR‐766‐3p, let‐7a‐5p, miR‐24‐3p, and miR‐1226‐5p. In qPCR validation, miR‐146a‐5p was increased, while let‐7a‐5p was decreased in responders compared with non‐responders. Multivariate logistic analysis illuminated that miR‐146a‐5p and CRP independently correlated with higher clinical response, while let‐7a‐5p and biologics history independently associated with lower clinical response. Subsequently, receiver operating characteristic curve showed that combination of these four independent factors presented with a great predictive value for clinical response with area under curve: 0.863, 95% CI 0.781‐0.945.

miRNA expression profile is closely implicated in the treatment efficacy of TNF inhibitor, and combined measurement of miR‐146a‐5p, let‐7a‐5p, CRP, and biologics history disclosed a great predictive value for clinical response to TNF inhibitor in RA patients.

• clinical response
• let-7a-5p
• miR-146a-5p
• miRNA expression profiles
• rheumatoid arthritis
• tumor necrosis factor inhibitor

• Fibroblast migration
• Integrin
• MMP9
• RECK isoforms
• Tubulin PTM

• MYC
• lncRNA
• miRNA
• ncRNA

• Biomarkers, Tumor/biosynthesis
• Biomarkers, Tumor/genetics
• Carcinogenesis/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasms/genetics
• Proto-Oncogene Proteins c-myc/biosynthesis
• Proto-Oncogene Proteins c-myc/genetics
• Proto-Oncogene Proteins c-myc/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism

• Lymph & Co
• 10478/2016-1 Dutch Cancer Society
• 2016/23/D/NZ1/01611 National Science Centre, Poland

• Migration
• Proliferation
• Quiescence
• Wound healing
• mRNA processing

• Cell Cycle
• Cell Movement
• Cells, Cultured
• Fibroblasts/cytology
• Fibroblasts/physiology
• Humans
• Poly A/genetics
• Poly A/metabolism
• Polyadenylation
• RNA Splicing
• Skin/cytology
• Skin/metabolism
• mRNA Cleavage and Polyadenylation Factors/genetics
• mRNA Cleavage and Polyadenylation Factors/metabolism

• T32AR071307 NIAMS NIH HHS
• AR070245 NIAMS NIH HHS
• 1 R01 CA221296-01A1 NCI NIH HHS
• UL1 TR000124 NCATS NIH HHS
• P50 GM071508 NIGMS NIH HHS
• UL1TR000124 NIH HHS
• R01 AR070245 NIAMS NIH HHS
• R01 CA221296 NCI NIH HHS
• UL1 TR001881 NCATS NIH HHS
• P30 CA016042 NCI NIH HHS
• GM081686 NIGMS NIH HHS
• T32 CA009056 NCI NIH HHS
• T32 AR071307 NIAMS NIH HHS
• GM0866465 NIGMS NIH HHS
• R01 GM081686 NIGMS NIH HHS
• Rita Allen Foundation
• National Science Foundation
• National Institute of General Medical Sciences
• National Institute of Arthritis and Musculoskeletal and Skin Diseases
• Pharmaceutical Research and Manufacturers of America Foundation
• Eli and Edythe Broad Foundation
• Iris Cantor Women's Health Center
• National Institutes of Health
• Leukemia and Lymphoma Society
• Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles
• National Cancer Institute
• Cancer Research Institute
• Melanoma Research Alliance
• Division of Cancer Epidemiology and Genetics, National Cancer Institute

• Lymnaea
• RNA sequencing
• growth cone
• microRNA
• neuronal regeneration
• retinoic acid

• Animals
• Central Nervous System
• Growth Cones/drug effects
• MicroRNAs/genetics
• MicroRNAs/physiology
• Mollusca/drug effects
• Mollusca/growth & development
• Neurons/drug effects
• Tretinoin/pharmacology

• biomarker
• chemotherapy
• miRNA
• radiation
• rectal cancer

• genetics
• issue 131
• transcript decay
• quiescence
• fibroblasts
• contact inhibition
• half-life
• actinomycin d
• mir-29

• Cell Proliferation/genetics
• Fibroblasts/cytology
• Fibroblasts/metabolism
• Fibroblasts/physiology
• Genomics
• Humans
• RNA Stability

• R01 GM086465 NIGMS NIH HHS
• UL1 TR000124 NCATS NIH HHS
• P50 CA092131 NCI NIH HHS
• P50 GM071508 NIGMS NIH HHS
• R01 GM081686 NIGMS NIH HHS
• UL1 TR001881 NCATS NIH HHS

• cell division cycle 34
• clinicopathological feature
• hepatitis C virus-positive hepatocellular carcinoma
• prognostic marker
• tumor suppressor

Quiescence, reversible exit from the cell division cycle, is characterized by large-scale changes in steady-state gene expression, yet mechanisms controlling these changes are in need of further elucidation. In order to characterize the effects of post-transcriptional control on the quiescent transcriptome in human fibroblasts, we determined mRNA decay rates for over 10,000 genes using a transcription shut-off time-course.

We found that ~500 of the genes monitored exhibited significant changes in decay rate upon quiescence induction. Genes involved in RNA processing and ribosome biogenesis were destabilized with quiescence, while genes involved in the developmental process were stabilized with quiescence. Moreover, extracellular matrix genes demonstrated an upregulation of gene expression that corresponded with a stabilization of these transcripts. Additionally, targets of a quiescence-associated microRNA (miR-29) were significantly enriched in the fraction of transcripts that were stabilized during quiescence.

Coordinated stability changes in clusters of genes with important functions in fibroblast quiescence maintenance are highly correlated with quiescence gene expression patterns. Analysis of miR-29 target decay rates suggests that microRNA-induced changes in RNA stability are important contributors to the quiescence gene expression program in fibroblasts. The identification of multiple stability-related gene clusters suggests that other posttranscriptional regulators of transcript stability may contribute to the coordination of quiescence gene expression. Such regulators may ultimately prove to be valuable targets for therapeutics that target proliferative cells, for instance, in cancer or fibrosis.

The online version of this article (doi:10.1186/s12864-017-3521-0) contains supplementary material, which is available to authorized users.

• Cell-cycle
• Gene expression
• Post-transcriptional regulation
• Quiescence
• mRNA stability
• miR-29

• Cell cycle
• Hif-1α
• Let-7b/7f
• Proliferation
• foxh1
• miRNA profile
• shRNA

• Antigens, CD/metabolism
• Carcinogenesis/pathology
• Cell Differentiation
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Polarity
• Cell Proliferation
• Cytokines/metabolism
• Down-Regulation/genetics
• Gene Expression Regulation, Neoplastic
• Human Umbilical Vein Endothelial Cells/metabolism
• Humans
• Inflammation/pathology
• Macrophages/metabolism
• Macrophages/pathology
• Male
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasm Invasiveness
• Neovascularization, Pathologic/genetics
• Phenotype
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology
• Up-Regulation/genetics

The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve using standard tissue biopsy techniques. Biological fluids such as blood hold great possibilities as a source of non-invasive cancer biomarkers that can act as surrogate markers to biopsy-based sampling. The non-invasive nature of these “liquid biopsies” ultimately means that cancer detection may be earlier and that the ability to monitor disease progression and/or treatment response represents a paradigm shift in the treatment of cancer patients. Below, we review one of the most promising classes of circulating cancer biomarkers: microRNAs (miRNAs). In particular, we will consider their history, the controversy surrounding their origin and biology, and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice.

• cfmiRNAs
• liquid biopsies
• miRNAs

• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• High-Throughput Nucleotide Sequencing
• Humans
• MicroRNAs/blood
• MicroRNAs/metabolism
• Neoplasms/diagnosis
• Real-Time Polymerase Chain Reaction

• Breast cancer
• Cell cycle
• Cell migration
• MicroRNAs
• Tumor associated macrophages

The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics.

DOI:http://dx.doi.org/10.7554/eLife.09431.001

The development of animals is guided by the expression of certain genes at critical moments. Many different mechanisms control development; in one of them, the expression of genes can be decreased by molecules called microRNAs. In particular, the group of microRNAs called let-7 has been intensively studied in roundworms and fruit flies. Although mammals have extremely similar let-7 microRNAs they seem to be more important during adulthood.

Previous studies using cells grown in the laboratory have shown that mammalian let-7 microRNAs decrease cell proliferation and cell growth. Furthermore, in mouse models of various cancers, let-7 microRNAs often reduce tumour growth when they are supplied to adult mice. Therefore, overall the let-7 group has been classified as genes that act to suppress tumors, and thus protect mice (and most likely humans too) from cancers. However, in-depth analysis of let-7 microRNAs was still missing.

Wu and Nguyen et al. have now studied mice with liver cancer using strains where they were able to regulate the levels of let-7. These mice overproduce a strong cancer-inducing gene in the liver; half were used as controls and the other half were further engineered to have moderately elevated levels of let-7 expression. Most of the control mice got large cancerous tumors, but only a few mice in the other group developed cancers and the tumors were smaller. This confirmed that let-7 hinders tumor formation.

Wu and Nguyen et al. also observed that the protected mice were less able to regenerate their liver tissues. Further experiments showed that deleting just two out of ten let-7 microRNAs enhanced the mice’s ability to regenerate liver tissue after injury. These findings indicate that let-7 microRNAs slow down the growth of both cancerous and normal cells. Lastly, when let-7 levels were raised to very high levels for a prolonged amount of time this actually led to liver damage and subsequent tumor formation.

This last observation may have important consequences for possible cancer therapies. Some scientists have shown that providing extra let-7 can slow or even reverse tumour growth, but the findings here clearly point out that too much let-7 could actually worsen the situation. Since the let-7 family comprises a handful of microRNAs in mammals, in the future it will also be important to find out to what extent these molecules play overlapping roles and how much they differ.

DOI:http://dx.doi.org/10.7554/eLife.09431.002

• MYC
• cancer
• cell biology
• developmental biology
• let-7
• liver
• microRNA
• mouse
• regeneration
• stem cells

• c-Myc
• induced pluripotent stem cell
• microRNA
• pluripotency

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder and is one of the most common forms of muscular dystrophy. We have recently shown that some hallmarks of FSHD are already expressed in fetal FSHD biopsies, thus opening a new field of investigation for mechanisms leading to FSHD. As microRNAs (miRNAs) play an important role in myogenesis and muscle disorders, in this study we compared miRNAs expression levels during normal and FSHD muscle development.

Muscle biopsies were obtained from quadriceps of both healthy control and FSHD1 fetuses with ages ranging from 14 to 33 weeks of development. miRNA expression profiles were analyzed using TaqMan Human MicroRNA Arrays.

During human skeletal muscle development, in control muscle biopsies we observed changes for 4 miRNAs potentially involved in secondary muscle fiber formation and 5 miRNAs potentially involved in fiber maturation. When we compared the miRNA profiles obtained from control and FSHD biopsies, we did not observe any differences in the muscle specific miRNAs. However, we identified 8 miRNAs exclusively expressed in FSHD1 samples (miR-330, miR-331-5p, miR-34a, miR-380-3p, miR-516b, miR-582-5p, miR-517* and miR-625) which could represent new biomarkers for this disease. Their putative targets are mainly involved in muscle development and morphogenesis. Interestingly, these FSHD1 specific miRNAs do not target the genes previously described to be involved in FSHD.

This work provides new candidate mechanisms potentially involved in the onset of FSHD pathology. Whether these FSHD specific miRNAs cause deregulations during fetal development, or protect against the appearance of the FSHD phenotype until the second decade of life still needs to be investigated.

• insulin signaling
• miRNA
• migration

• Lin28
• Wilms tumor
• kidney development

• Animals
• Cell Differentiation
• Gene Expression
• Gene Expression Regulation, Developmental
• Humans
• Kidney/embryology
• Kidney Neoplasms/genetics
• Kidney Neoplasms/physiopathology
• Mice
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/metabolism
• Stem Cells/cytology
• Wilms Tumor/genetics
• Wilms Tumor/physiopathology

• 17297 Cancer Research UK
• F31 CA186444 NCI NIH HHS
• K08 CA157727 NCI NIH HHS
• Howard Hughes Medical Institute

The messenger RNA 3’-untranslated region (3’UTR) plays an important role in regulation of gene expression on the posttranscriptional level. The 3’UTR controls gene expression via orchestrated interaction between the structural components of mRNAs (cis-element) and the specific trans-acting factors (RNA binding proteins and non-coding RNAs). The crosstalk of these factors is based on the binding sequences and/or direct protein-protein interaction, or just functional interaction. Much new evidence that has accumulated supports the idea that several RNA binding factors can bind to common mRNA targets: to the non-overlapping binding sites or to common sites in a competitive fashion. Various factors capable of binding to the same RNA can cooperate or be antagonistic in their actions. The outcome of the collective function of all factors bound to the same mRNA 3’UTR depends on many circumstances, such as their expression levels, affinity to the binding sites, and localization in the cell, which can be controlled by various physiological conditions. Moreover, the functional and/or physical interactions of the factors binding to 3’UTR can change the character of their actions. These interactions vary during the cell cycle and in response to changing physiological conditions. Abnormal functioning of the factors can lead to disease. In this review we will discuss how alterations of these factors or their interaction can affect cancer development and promote or enhance the malignant phenotype of cancer cells. Understanding these alterations and their impact on 3’UTR-directed posttranscriptional gene regulation will uncover promising new targets for therapeutic intervention and diagnostics. We will also discuss emerging new tools in cancer diagnostics and therapy based on 3’UTR binding factors and approaches to improve them.

• Translational control
• 3’-untranslated region
• MicroRNAs
• RNA binding proteins
• Cancer

• cellular lifespan
• let-7a
• p66Shc
• replicative senescence
• translational regulation

Embryonic and induced pluripotent stem cells (ESCs and iPSCs) hold great promise for regenerative medicine. The therapeutic application of these cells requires an understanding of the molecular networks that regulate pluripotency, differentiation, and de-differentiation. Along with signaling pathways, transcription factors, and epigenetic regulators, microRNAs (miRNAs) are emerging as important regulators in the establishment and maintenance of pluripotency. These tiny RNAs control proliferation, survival, the cell cycle, and the pluripotency program of ESCs. In addition, they serve as barriers or factors to overcome barriers during the reprogramming process. Systematic screening for novel miRNAs that regulate the establishment and maintenance of pluripotent stem cells and further mechanistic investigations will not only shed new light on the biology of ESCs and iPSCs, but also help develop safe and efficient technologies to manipulate cell fate for regenerative medicine.

• Slug
• epithelial-to-mesenchymal transition
• fibrosis
• high-mobility group-A2 protein
• idiopathic pulmonary fibrosis
• microRNA
• transforming growth factor-β

• Adrenal Cortex Neoplasms/genetics
• Cell Cycle/drug effects
• Computational Biology
• Databases, Genetic
• Down-Regulation
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Metabolic Networks and Pathways/genetics
• MicroRNAs/genetics
• MicroRNAs/physiology
• RNA, Messenger/genetics
• Signal Transduction/drug effects
• Tretinoin/physiology
• Up-Regulation

• Adult
• Aged
• Basigin/metabolism
• Biomarkers, Tumor/metabolism
• Breast Diseases/diagnosis
• Breast Diseases/metabolism
• Breast Neoplasms/diagnosis
• Breast Neoplasms/metabolism
• Breast Neoplasms/mortality
• Digoxigenin
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/metabolism
• Middle Aged
• Oligonucleotide Probes
• Prognosis
• Retrospective Studies
• Treatment Outcome

• Blotting, Western
• Cell Differentiation
• Cell Proliferation
• Cells, Cultured
• Cellular Reprogramming
• Early Growth Response Protein 1/genetics
• Early Growth Response Protein 1/metabolism
• Fluorescent Antibody Technique
• Humans
• Induced Pluripotent Stem Cells/cytology
• Induced Pluripotent Stem Cells/metabolism
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors/genetics
• Kruppel-Like Transcription Factors/metabolism
• MicroRNAs/genetics
• Octamer Transcription Factor-3/genetics
• Octamer Transcription Factor-3/metabolism
• Proto-Oncogene Proteins c-myc/genetics
• Proto-Oncogene Proteins c-myc/metabolism
• RNA, Messenger/genetics
• RNA, Small Interfering/genetics
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• SOXB1 Transcription Factors/genetics
• SOXB1 Transcription Factors/metabolism
• Tripartite Motif Proteins
• Ubiquitin-Protein Ligases/antagonists & inhibitors
• Ubiquitin-Protein Ligases/genetics
• Ubiquitin-Protein Ligases/metabolism

• U01 HL098179 NHLBI NIH HHS
• F32 GM088988 NIGMS NIH HHS
• U01 HL100406 NHLBI NIH HHS
• U01-HL100406 NHLBI NIH HHS
• F32GM88988-02 NIGMS NIH HHS
• C06 RR018928 NCRR NIH HHS
• RR18928-01 NCRR NIH HHS
• U01-HL098179 NHLBI NIH HHS

Over the two past decades, a significant number of studies have observed animal growth traits to examine animal genetic mechanisms due to their ease of measurement and high heritability. Chicken which has a significant impact on fundamental biology is a major source of protein worldwide, making it an ideal model for examining animal growth trait development. The genetic mechanisms of chicken growth traits have been studied using quantitative trait loci mapping through genome-scan and candidate gene approaches, genome-wide association studies (GWAS), comparative genomic strategies, microRNA (miRNA) regulation of growth development analysis, and epigenomic analysis. This review focuses on chicken GWAS and miRNA regulation of growth traits. Several recently published GWAS reports showed that most genome-wide significant single nucleotide polymorphisms are located on chromosomes 1 and 4 in chickens. Chicken growth, particularly skeletal muscle growth and development, is greatly regulated by miRNA. Using dwarf and normal chickens, let-7b was found to be involved in determining chicken dwarf phenotypes by regulating growth hormone receptor gene expression.

• Chicken
• Genome-wide association study (GWAS)
• Growth traits
• Quantitative trait loci (QTL)
• Single nucleotide polymorphisms (SNPs).
• microRNA (miRNA) regulation

The methylation state of K20 on histone H4 is important for proper cell cycle control and chromatin compaction in human fibroblasts. High levels of dimethylated and trimethylated K20 are associated with quiescence, and loss of these modifications causes a more open chromatin conformation and defects in cell cycle progression and exit.

The transition between proliferation and quiescence is frequently associated with changes in gene expression, extent of chromatin compaction, and histone modifications, but whether changes in chromatin state actually regulate cell cycle exit with quiescence is unclear. We find that primary human fibroblasts induced into quiescence exhibit tighter chromatin compaction. Mass spectrometry analysis of histone modifications reveals that H4K20me2 and H4K20me3 increase in quiescence and other histone modifications are present at similar levels in proliferating and quiescent cells. Analysis of cells in S, G₂/M, and G₁ phases shows that H4K20me1 increases after S phase and is converted to H4K20me2 and H4K20me3 in quiescence. Knockdown of the enzyme that creates H4K20me3 results in an increased fraction of cells in S phase, a defect in exiting the cell cycle, and decreased chromatin compaction. Overexpression of Suv4-20h1, the enzyme that creates H4K20me2 from H4K20me1, results in G₂ arrest, consistent with a role for H4K20me1 in mitosis. The results suggest that the same lysine on H4K20 may, in its different methylation states, facilitate mitotic functions in M phase and promote chromatin compaction and cell cycle exit in quiescent cells.

MicroRNAs (miRNAs) are a large family of endogenous, non-coding RNAs, about 22 nucleotides long, which regulate gene expression through sequence-specific base pairing with target mRNAs. Extensive studies have shown that miRNA expression in the skin changes remarkably during distinct stages of the hair cycle in humans, mice, goats and sheep.

In this study, the skin tissues were harvested from the three stages of hair follicle cycling (anagen, catagen and telogen) in a fibre-producing goat breed. In total, 63,109,004 raw reads were obtained by Solexa sequencing and 61,125,752 clean reads remained for the small RNA digitalisation analysis. This resulted in the identification of 399 conserved miRNAs; among these, 326 miRNAs were expressed in all three follicular cycling stages, whereas 3, 12 and 11 miRNAs were specifically expressed in anagen, catagen, and telogen, respectively. We also identified 172 potential novel miRNAs by Mireap, 36 miRNAs were expressed in all three cycling stages, whereas 23, 29 and 44 miRNAs were specifically expressed in anagen, catagen, and telogen, respectively. The expression level of five arbitrarily selected miRNAs was analyzed by quantitative PCR, and the results indicated that the expression patterns were consistent with the Solexa sequencing results. Gene Ontology and KEGG pathway analyses indicated that five major biological pathways (Metabolic pathways, Pathways in cancer, MAPK signalling pathway, Endocytosis and Focal adhesion) accounted for 23.08% of target genes among 278 biological functions, indicating that these pathways are likely to play significant roles during hair cycling.

During all hair cycle stages of cashmere goats, a large number of conserved and novel miRNAs were identified through a high-throughput sequencing approach. This study enriches the Capra hircus miRNA databases and provides a comprehensive miRNA transcriptome profile in the skin of goats during the hair follicle cycle.

• Animals
• Cell Cycle/genetics
• Cell Proliferation
• Embryonic Development/genetics
• Gene Expression Regulation
• Humans
• RNA-Binding Proteins/metabolism
• Stem Cells/cytology
• Stem Cells/metabolism

• Howard Hughes Medical Institute
• U01 HL100001 NHLBI NIH HHS
• U01-HL100001 NHLBI NIH HHS

Overexpression of ribonucleotide reductase subunit M2 (RRM2), involved in deoxyribonucleotide synthesis, drives the chemoresistance of pancreatic cancer to nucleoside analogs (e.g., gemcitabine). While silencing RRM2 by synthetic means has shown promise in reducing chemoresistance, targeting endogenous molecules, especially microRNAs (miRNAs), to advance chemotherapeutic outcomes has been poorly explored. Based on computational predictions, we hypothesized that the let-7 tumor suppressor miRNAs will inhibit RRM2-mediated gemcitabine chemoresistance in pancreatic cancer. Reduced expression of the majority of let-7 miRNAs with an inverse relationship to RRM2 expression was identified in innately gemcitabine-resistant pancreatic cancer cell lines. Direct binding of let-7 miRNAs to the 3′ UTR of RRM2 transcripts identified post-transcriptional regulation of RRM2 influencing gemcitabine chemosensitivity. Intriguingly, overexpression of human precursor-let-7 miRNAs led to differential RRM2 expression and chemosensitivity responses in a poorly differentiated pancreatic cancer cell line, MIA PaCa-2. Defective processing of let-7a precursors to mature forms, in part, explained the discrepancies observed with let-7a expressional outcomes. Consistently, the ratios of mature to precursor let-7a were progressively reduced in gemcitabine-sensitive L3.6pl and Capan-1 cell lines induced to acquire gemcitabine resistance. Besides known regulators of let-7 biogenesis (e.g., LIN-28), short hairpin RNA library screening identified several novel RNA binding proteins, including the SET oncoprotein, to differentially impact let-7 biogenesis and chemosensitivity in gemcitabine-sensitive versus -resistant pancreatic cancer cells. Further, LIN-28 and SET knockdown in the cells led to profound reductions in cellular proliferation and colony-formation capacities. Finally, defective processing of let-7a precursors with a positive correlation to RRM2 overexpression was identified in patient-derived pancreatic ductal adenocarcinoma (PDAC) tissues. These data demonstrate an intricate post-transcriptional regulation of RRM2 and chemosensitivity by let-7a and that the manipulation of regulatory proteins involved in let-7a transcription/processing may provide a mechanism for improving chemotherapeutic and/or tumor growth control responses in pancreatic cancer.

• Antineoplastic Agents/pharmacology
• Cell Line
• Cells, Cultured
• DNA-Binding Proteins
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/pharmacology
• Drug Resistance, Neoplasm/genetics
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Histone Chaperones/metabolism
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Oncogene Proteins/metabolism
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• RNA Interference
• RNA-Binding Proteins/metabolism
• Ribonucleoside Diphosphate Reductase/genetics
• Transcription Factors/metabolism
• Gemcitabine

• P50 CA128613 NCI NIH HHS
• R03 CA161832 NCI NIH HHS
• 5-P50-CA128613-SPORE NCI NIH HHS
• 1R03CA161832-01 NCI NIH HHS

Although quiescence (reversible cell cycle arrest) is a key part in the life history and fate of many mammalian cell types, the mechanisms of gene regulation in quiescent cells are poorly understood. We sought to clarify the role of microRNAs as regulators of the cellular functions of quiescent human fibroblasts.

Using microarrays, we discovered that the expression of the majority of profiled microRNAs differed between proliferating and quiescent fibroblasts. Fibroblasts induced into quiescence by contact inhibition or serum starvation had similar microRNA profiles, indicating common changes induced by distinct quiescence signals. By analyzing the gene expression patterns of microRNA target genes with quiescence, we discovered a strong regulatory function for miR-29, which is downregulated with quiescence. Using microarrays and immunoblotting, we confirmed that miR-29 targets genes encoding collagen and other extracellular matrix proteins and that those target genes are induced in quiescence. In addition, overexpression of miR-29 resulted in more rapid cell cycle re-entry from quiescence. We also found that let-7 and miR-125 were upregulated in quiescent cells. Overexpression of either one alone resulted in slower cell cycle re-entry from quiescence, while the combination of both together slowed cell cycle re-entry even further.

microRNAs regulate key aspects of fibroblast quiescence including the proliferative state of the cells as well as their gene expression profiles, in particular, the induction of extracellular matrix proteins in quiescent fibroblasts.

• Animals
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation/drug effects
• HCT116 Cells
• HT29 Cells
• Humans
• Mice
• MicroRNAs/physiology
• NF-kappa B/antagonists & inhibitors
• Neoplasm Invasiveness
• Triterpenes/pharmacology