Reevaluation by the CRISPR/Cas9 knockout approach revealed that multiple pluripotency-associated lncRNAs are dispensable for pluripotency maintenance while Snora73a/b is essential for pluripotency exit.

Many long noncoding RNAs (lncRNAs) have been identified through siRNA-based screening as essential regulators of embryonic stem cell (ESC) pluripotency. However, the biological and molecular functions of most lncRNAs remain unclear. Here, we employed CRISPR/Cas9-mediated knockout technology to explore the functions of 8 lncRNAs previously reported to promote pluripotency in mouse ESCs. Unexpectedly, all of these lncRNAs were dispensable for pluripotency maintenance and proliferation in mouse ESCs when disrupted individually or in combination. Single-cell transcriptomic analysis also showed that the knockout of these lncRNAs has a minimal impact on pluripotency gene expression and cell identity. We further showed that several small hairpin RNAs (shRNAs) previously used to knock down lncRNAs caused the downregulation of pluripotency genes in the corresponding lncRNA-knockout ESCs, indicating that off-target effects likely responsible for the pluripotency defects caused by these shRNAs. Interestingly, linc1343-knockout and linc1343-knockdown ESCs failed to form cystic structures and exhibited high expression of pluripotency genes during embryoid body (EB) differentiation. By reintroducing RNA products generated from the linc1343 locus, we found that two snoRNAs, Snora73a and Snora73b, but not lncRNAs, could rescue pluripotency silencing defects during EB differentiation of linc1343 knockout ESCs. Our results suggest that the 8 previously annotated pluripotency-regulating lncRNAs have no overt functions in conventional ESC culture; however, we identified snoRNA products derived from an annotated lncRNA locus as essential regulators for silencing pluripotency genes.

Molecular mechanism governing RNA-binding property of mammalian TRIM71 protein.

TRIM71 is an RNA-binding protein with ubiquitin ligase activity. Numerous functions of mammalian TRIM71, including cell cycle regulation, embryonic stem cell (ESC) self-renewal, and reprogramming of pluripotent stem cells, are related to its RNA-binding property. We previously reported that a long noncoding RNA (lncRNA) Trincr1 interacts with mouse TRIM71 (mTRIM71) to repress FGF/ERK pathway in mouse ESCs (mESCs). Herein, we identify an RNA motif specifically recognized by mTRIM71 from Trincr1 RNA, and solve the crystal structure of the NHL domain of mTRIM71 complexed with the RNA motif. Similar to the zebrafish TRIM71, mTRIM71 binds to a stem-loop structured RNA fragment of Trincr1, and an adenosine base at the loop region is crucial for the mTRIM71 interaction. We map similar hairpin RNAs preferably bound by TRIM71 in the mRNA UTRs of the cell-cycle related genes regulated by TRIM71. Furthermore, we identify key residues of mTRIM71, conserved among mammalian TRIM71 proteins, required for the RNA-binding property. Single-site mutations of these residues significantly impair the binding of TRIM71 to hairpin RNAs in vitro and to mRNAs of Cdkn1a/p21 and Rbl2/p130 in mESCs. Furthermore, congenital hydrocephalus (CH) specific mutation of mTRIM71 impair its binding to the RNA targets as well. These results reveal molecular mechanism behind the recognition of RNA by mammalian TRIM71 and provide insights into TRIM71 related diseases.

miRNA dosage control in development and human disease.

In mammals, miRNAs recognize target mRNAs via base pairing, which leads to a complex 'multiple-to-multiple' regulatory network. Previous studies have focused on the regulatory mechanisms and functions of individual miRNAs, but alterations of many individual miRNAs do not strongly disturb the miRNA regulatory network. Recent studies revealed the important roles of global miRNA dosage control events in physiological processes and pathogenesis, suggesting that miRNAs can be considered as a 'cellular buffer' that controls cell fate. Here, we review the current state of research on how global miRNA dosage is tightly controlled to regulate development, tumorigenesis, neurophysiology, and immunity. We propose that methods of controlling global miRNA dosage may serve as effective therapeutic tools to cure human diseases.

MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice.

Intestinal epithelium undergoes regeneration after injuries, and the disruption of this process can lead to inflammatory bowel disease and tumorigenesis. Intestinal stem cells (ISCs) residing in the crypts are crucial for maintaining the intestinal epithelium's homeostasis and promoting regeneration upon injury. However, the precise role of DGCR8, a critical component in microRNA (miRNA) biogenesis, in intestinal regeneration remains poorly understood. In this study, we provide compelling evidence demonstrating the indispensable role of epithelial miRNAs in the regeneration of the intestine in mice subjected to 5-FU or irradiation-induced injury. Through a comprehensive pooled screen of miRNA function in Dgcr8-deficient organoids, we observe that the loss of the miR-200 family leads to the hyperactivation of the p53 pathway, thereby reducing ISCs and impairing epithelial regeneration. Notably, downregulation of the miR-200 family and hyperactivation of the p53 pathway are verified in colonic tissues from patients with active ulcerative colitis (UC). Most importantly, the transient supply of miR-200 through the oral delivery of lipid nanoparticles (LNPs) carrying miR-200 restores ISCs and promotes intestinal regeneration in mice following acute injury. Our study implies the miR-200/p53 pathway as a promising therapeutic target for active UC patients with diminished levels of the miR-200 family. Furthermore, our findings suggest that the clinical application of LNP-miRNAs could enhance the efficacy, safety, and acceptability of existing therapeutic modalities for intestinal diseases.

Large anomalous Nernst effect and nodal plane in an iron-based kagome ferromagnet.

Anomalous Nernst effect (ANE), converting a heat flow to transverse electric voltage, originates from the Berry phase of electronic wave function near the Fermi energy EF. Thus, the ANE provides a sensitive probe to detect a topological state that produces large Berry curvature. In addition, a magnet that exhibits a large ANE using low-cost and safe elements will be useful to develop a novel energy harvesting technology. Here, we report our observation of a high ANE exceeding 3 microvolts per kelvin above room temperature in the kagome ferromagnet Fe3Sn with the Curie temperature of 760 kelvin. Our theoretical analysis clarifies that a "nodal plane" produces a flat hexagonal frame with strongly enhanced Berry curvature, resulting in the large ANE. Our discovery of the large ANE in Fe3Sn opens the path for the previously unexplored functionality of flat degenerate electronic states and for developing flexible film thermopile and heat current sensors.

Fine mapping of the BnaC04.BIL1 gene controlling plant height in Brassica napus L.

BACKGROUND: Plant height is an important architecture trait which is a fundamental yield-determining trait in crops. Variety with dwarf or semi-dwarf phenotype is a major objective in the breeding because dwarfing architecture can help to increase harvest index, increase planting density, enhance lodging resistance, and thus be suitable for mechanization harvest. Although some germplasm or genes associated with dwarfing plant type have been carried out. The molecular mechanisms underlying dwarfism in oilseed rape (Brassica napus L.) are poorly understood, restricting the progress of breeding dwarf varieties in this species. Here, we report a new dwarf mutant Bndwarf2 from our B. napus germplasm. We studied its inheritance and mapped the dwarf locus BnDWARF2. RESULTS: The inheritance analysis showed that the dwarfism phenotype was controlled by one semi-dominant gene, which was mapped in an interval of 787.88 kb on the C04 chromosome of B. napus by Illumina Brassica 60 K Bead Chip Array. To fine-map BnDWARF2, 318 simple sequence repeat (SSR) primers were designed to uniformly cover the mapping interval. Among them, 15 polymorphic primers that narrowed down the BnDWARF2 locus to 34.62 kb were detected using a F2:3 family population with 889 individuals. Protein sequence analysis showed that only BnaC04.BIL1 (BnaC04g41660D) had two amino acid residues substitutions (Thr187Ser and Gln399His) between ZS11 and Bndwarf2, which encoding a GLYCOGEN SYNTHASE KINASE 3 (GSK3-like). The quantitative real-time PCR (qRT-PCR) analysis showed that the BnaC04.BIL1 gene expressed in all tissues of oilseed rape. Subcellular localization experiment showed that BnaC04.BIL1 was localized in the nucleus in tobacco leaf cells. Genetic transformation experiments confirmed that the BnaC04.BIL1 is responsible for the plant dwarf phenotype in the Bndwarf2 mutants. Overexpression of BnaC04.BIL1 reduced plant height, but also resulted in compact plant architecture. CONCLUSIONS: A dominant dwarfing gene, BnaC04.BIL1, encodes an GSK3-like that negatively regulates plant height, was mapped and isolated. Our identification of a distinct gene locus may help to improve lodging resistance in oilseed rape.

Acidic pH transiently prevents the silencing of self-renewal and dampens microRNA function in embryonic stem cells.

Enhanced glycolysis is a distinct feature associated with numerous stem cells and cancer cells. However, little is known about its regulatory roles in gene expression and cell fate determination. Here, we confirm that glycolytic metabolism and lactate production decrease during the differentiation of mouse embryonic stem cells (mESCs). Importantly, acidic pH due to lactate accumulation can transiently prevent the silencing of mESC self-renewal in differentiation conditions. Furthermore, acidic pH partially blocks the differentiation of human ESCs (hESCs). Mechanistically, acidic pH downregulates AGO1 protein and de-represses a subset of mRNA targets of miR-290/302 family of microRNAs which facilitate the exit of naive pluripotency state in mESCs. Interestingly, AGO1 protein is also downregulated by acidic pH in cancer cells. Altogether, this study provides insights into the potential function and underlying mechanism of acidic pH in pluripotent stem cells (PSCs).

Author Correction: Iron-based binary ferromagnets for transverse thermoelectric conversion.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Iron-based binary ferromagnets for transverse thermoelectric conversion.

Thermoelectric generation using the anomalous Nernst effect (ANE) has great potential for application in energy harvesting technology because the transverse geometry of the Nernst effect should enable efficient, large-area and flexible coverage of a heat source. For such applications to be viable, substantial improvements will be necessary not only for their performance but also for the associated material costs, safety and stability. In terms of the electronic structure, the anomalous Nernst effect (ANE) originates from the Berry curvature of the conduction electrons near the Fermi energy1,2. To design a large Berry curvature, several approaches have been considered using nodal points and lines in momentum space3-10. Here we perform a high-throughput computational search and find that 25 percent doping of aluminium and gallium in alpha iron, a naturally abundant and low-cost element, dramatically enhances the ANE by a factor of more than ten, reaching about 4 and 6 microvolts per kelvin at room temperature, respectively, close to the highest value reported so far. The comparison between experiment and theory indicates that the Fermi energy tuning to the nodal web-a flat band structure made of interconnected nodal lines-is the key for the strong enhancement in the transverse thermoelectric coefficient, reaching a value of about 5 amperes per kelvin per metre with a logarithmic temperature dependence. We have also succeeded in fabricating thin films that exhibit a large ANE at zero field, which could be suitable for designing low-cost, flexible microelectronic thermoelectric generators11-13.

NEAT1 scaffolds RNA-binding proteins and the Microprocessor to globally enhance pri-miRNA processing.

MicroRNA (miRNA) biogenesis is known to be modulated by a variety of RNA-binding proteins (RBPs), but in most cases, individual RBPs appear to influence the processing of a small subset of target miRNAs. Here, we report that the RNA-binding NONO-PSF heterodimer binds a large number of expressed pri-miRNAs in HeLa cells to globally enhance pri-miRNA processing by the Drosha-DGCR8 Microprocessor. NONO and PSF are key components of paraspeckles organized by the long noncoding RNA (lncRNA) NEAT1. We further demonstrate that NEAT1 also has a profound effect on global pri-miRNA processing. Mechanistic dissection reveals that NEAT1 broadly interacts with the NONO-PSF heterodimer as well as many other RBPs and that multiple RNA segments in NEAT1, including a 'pseudo pri-miRNA' near its 3' end, help attract the Microprocessor. These findings suggest a 'bird nest' model in which an lncRNA orchestrates efficient processing of potentially an entire class of small noncoding RNAs in the nucleus.

Danshen-Enhanced Cardioprotective Effect of Cardioplegia on Ischemia Reperfusion Injury in a Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Model.

Myocardial ischemia-reperfusion (I/R) injury is unavoidable during cardioplegic arrest and open-heart surgery. Danshen is one of the most popular traditional herbal medicines in China, which has entered the Food and Drug Administration-approved phase III clinical trial. This study was aimed to develop a human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) model to mimic I/R injury and evaluate the cardioprotective effect of regular cardioplegic solution with Danshen. hiPSC-CMs were cultured with the crystalloid cardioplegic solution (Thomas group) and Thomas solution with 2 or 10 µg/mL Danshen (Thomas plus Danshen groups). The cells under normoxic culture condition served as baseline group. Then, the cells were placed in a modular incubator chamber. After 45 min hypoxia and 3 h reoxygenation, hiPSC-CMs subjected to hypoxia/reoxygenation resulted in a sharp increase of reactive oxygen species (ROS) content in Thomas group versus baseline group. Compared with the Thomas group, ROS accumulation was significant suppressed in Thomas plus Danshen groups, which might result from elevating the content of glutathione and enhanced activities of superoxide dismutase and glutathione peroxidase. The enhanced L-type Ca2+ current in hiPSC-CMs after I/R injury was also significantly decreased by Danshen, and meanwhile intracellular Ca2+ level was reduced and calcium overload was suppressed. Thomas plus Danshen groups also presented less irregular transients and lower apoptosis rates. As a result, Danshen could improve antioxidant and calcium handling in cardiomyocytes during I/R and lead to reduced arrhythmia events and apoptosis rates. hiPSC-CMs model offered a platform for the future translational study of the cardioplegia.

Pluripotency-associated miR-290/302 family of microRNAs promote the dismantling of naive pluripotency.

The molecular mechanism controlling the dismantling of naive pluripotency is poorly understood. Here we show that microRNAs (miRNAs) have important roles during naive to primed pluripotency transition. Dgcr8(-/-) embryonic stem cells (ESCs) failed to completely silence the naive pluripotency program, as well as to establish the primed pluripotency program during differentiation. miRNA profiling revealed that expression levels of a large number of miRNAs changed dynamically and rapidly during naive to primed pluripotency transition. Furthermore, a miRNA screen identified numerous miRNAs promoting naive to primed pluripotency transition. Unexpectedly, multiple miRNAs from miR-290 and miR-302 clusters, previously shown as pluripotency-promoting miRNAs, demonstrated the strongest effects in silencing naive pluripotency. Knockout of both miR-290 and miR-302 clusters but not either alone blocked the silencing of naive pluripotency program. Mechanistically, the miR-290/302 family of miRNAs may facilitate the exit of naive pluripotency in part by promoting the activity of MEK pathway and through directly repressing Akt1. Our study reveals miRNAs as an important class of regulators potentiating ESCs to transition from naive to primed pluripotency, and uncovers context-dependent functions of the miR-290/302 family of miRNAs at different developmental stages.

Low BIK outside-inside-out interactive inflammation immune-induced transcription-dependent apoptosis through FUT3-PMM2-SQSTM1-SFN-ZNF384.

Eighteen different Pearson mutual-positive-correlation BIK-activatory molecular feedback upstream and downstream networks were constructed from 79 overlapping of 376 GRNInfer and 98 Pearson under BIK CC ≥ 0.25 in low normal adjacent tissues of Taiwan compared with high lung adenocarcinoma. Our identified BIK interactive total feedback molecular network showed FUT3 [fucosyltransferase 3 (galactoside 3(4)-L-fucosyltransferase Lewis blood group)], PMM2 (phosphomannomutase 2), SQSTM1 (sequestosome 1), SFN_2 [REX2 RNA exonuclease 2 homolog (S. cerevisiae)] and ZNF384 (zinc finger protein 384) in low normal adjacent tissues of lung adenocarcinoma. BIK interactive total feedback terms included mitochondrial envelope, endomembrane system, integral to membrane, Golgi apparatus, cytoplasm, nucleus, cytosol, intracellular signaling cascade, mitochondrion, extracellular space, inflammation, immune response, apoptosis, cell differentiation, cell cycle, regulation of cell cycle, cell proliferation, estrogen-responsive protein Efp controls cell cycle and breast tumors growth, induction or regulation of apoptosis based on integrative GO, KEGG, GenMAPP, BioCarta and disease databases in low normal adjacent tissues of lung adenocarcinoma. Therefore, we propose low BIK outside-inside-out interactive inflammation immune-induced transcription-dependent apoptosis through FUT3-PMM2-SQSTM1-SFN-ZNF384 in normal adjacent tissues of lung adenocarcinoma.

High EGFR_1 Inside-Out Activated Inflammation-Induced Motility through SLC2A1-CCNB2-HMMR-KIF11-NUSAP1-PRC1-UBE2C.

48 different Pearson mutual-positive-correlation epidermal growth factor receptor (EGFR_1)-activatory molecular feedback, up- and down-stream network was constructed from 171 overlapping of 366 GRNInfer and 223 Pearson under EGFR_1 CC ≥0.25 in high lung adenocarcinoma compared with low human normal adjacent tissues. Our identified EGFR_1 inside-out upstream activated molecular network showed SLC2A1 (solute carrier family 2 (facilitated glucose transporter) member 1), CCNB2 (cyclin B2), HMMR (hyaluronan-mediated motility receptor (RHAMM)), KIF11 (kinesin family member 11), NUSAP1 (nucleolar and spindle associated protein 1), PRC1 (protein regulator of cytokinesis 1), UBE2C (ubiquitin-conjugating enzyme E2C) in high lung adenocarcinoma. EGFR_1 inside-out upstream activated terms network includes intracellular, membrane fraction, cytoplasm, plasma membrane, integral to membrane, basolateral plasma membrane, transmembrane transport, nucleus, cytosol, cell surface; T cell homeostasis, inflammation; microtubule cytoskeleton, embryonic development (sensu Mammalia), cell cycle, mitosis, thymus development, cell division, regulation of cell cycle, Contributed--cellular process--Hs cell cycle KEGG, cytokinesis, M phase, M phase of mitotic cell cycle, estrogen-responsive protein Efp controls cell cycle and breast tumors growth, cell motility, locomotion, locomotory behavior, neoplasm metastasis, spindle pole, spindle microtubule, microtubule motor activity, microtubule-based movement, mitotic spindle organization and biogenesis, mitotic centrosome separation, spindle pole body organization and biogenesis, microtubule-based process, microtubule, cytokinesis after mitosis, mitotic chromosome condensation, establishment of mitotic spindle localization, positive regulation of mitosis, mitotic spindle elongation, spindle organization and biogenesis, positive regulation of exit from mitosis, regulation of cell proliferation, positive regulation of cell proliferation based on integrative GO, KEGG, GenMAPP, BioCarta and disease databases in high lung adenocarcinoma. Therefore, we propose high EGFR_1 inside-out activated inflammation-induced motility through SLC2A1-CCNB2-HMMR-KIF11-NUSAP1-PRC1-UBE2C in lung adenocarcinoma.

miR-290/371-Mbd2-Myc circuit regulates glycolytic metabolism to promote pluripotency.

Enhanced glycolysis is a main feature of pluripotent stem cells (PSCs) and is proposed to be important for the maintenance and induction of pluripotency. The molecular mechanism underlying enhanced glycolysis in PSCs is not clear. Using Dgcr8-/- mouse embryonic stem cells (ESCs) that lack mature miRNAs, we found that miR-290 cluster of miRNAs stimulates glycolysis by upregulating glycolytic enzymes Pkm2 and Ldha, which are also essential for the induction of pluripotency during reprogramming. Mechanistically, we identified Mbd2, a reader for methylated CpGs, as the target of miR-290 cluster that represses glycolysis and reprogramming. Furthermore, we discovered Myc as a key target of Mbd2 that controls metabolic switch in ESCs. Importantly, we demonstrated that miR-371 cluster, a human homolog of miR-290 cluster, stimulates glycolysis to promote the reprogramming of human fibroblasts. Hence, we identified a previously unappreciated mechanism by which miR-290/371 miRNAs orchestrate epigenetic, transcriptional and metabolic networks to promote pluripotency in PSCs and during reprogramming.

Low glucose transporter SLC2A5-inhibited human normal adjacent lung adenocarcinoma cytoplasmic pro-B cell development mechanism network.

Solute carrier family 2 (facilitated glucose/fructose transporter) member 5 (SLC2A5)-inhibited seven different molecular Pearson mutual-positive-correlation networks constructed by 24 overlapping molecules from 368 GRNInfer and 34 Pearson under SLC2A5 CC ≤-0.25 in low human normal adjacent tissues were compared with high lung adenocarcinoma. Based on GO, KEGG, GenMAPP, BioCarta, and disease databases, our result showed that low SLC2A5-inhibited network included Golgi apparatus of AP1M2_1; cell cycle of CUL7, SAC3D1; protein amino acid dephosphorylation of STYXL1; pro-B cell-cell differentiation of SOX4_3; and FAD biosynthesis of FLAD1. Thus, we propose low glucose transporter SLC2A5-inhibited human normal adjacent lung adenocarcinoma cytoplasmic pro-B cell development mechanism network through repression of protein amino acid dephosphorylation to FAD biosynthesis.

Functional screen reveals essential roles of miR-27a/24 in differentiation of embryonic stem cells.

MicroRNAs play important roles in controlling the embryonic stem cell (ESC) state. Although much is known about microRNAs maintaining ESC state, microRNAs that are responsible for promoting ESC differentiation are less reported. Here, by screening 40 microRNAs pre-selected by their expression patterns and predicted targets in Dgcr8-null ESCs, we identify 14 novel differentiation-associated microRNAs. Among them, miR-27a and miR-24, restrained by c-Myc in ESC, exert their roles of silencing self-renewal through directly targeting several important pluripotency-associated factors, such as Oct4, Foxo1 and Smads. CRISPR/Cas9-mediated knockout of all miR-27/24 in ESCs leads to serious deficiency in ESC differentiation in vitro and in vivo. Moreover, depleting of them in mouse embryonic fibroblasts can evidently promote somatic cell reprogramming. Altogether, our findings uncover the essential role of miR-27 and miR-24 in ESC differentiation and also demonstrate novel microRNAs responsible for ESC differentiation.

Micro-management of pluripotent stem cells.

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.

miR-294/miR-302 promotes proliferation, suppresses G1-S restriction point, and inhibits ESC differentiation through separable mechanisms.

The miR-294 and miR-302 microRNAs promote the abbreviated G1 phase of the embryonic stem cell (ESC) cell cycle and suppress differentiation induced by let-7. Here, we evaluated the role of the retinoblastoma (Rb) family proteins in these settings. Under normal growth conditions, miR-294 promoted the rapid G1-S transition independent of the Rb family. In contrast, miR-294 suppressed the further accumulation of cells in G1 in response to nutrient deprivation and cell-cell contact in an Rb-dependent fashion. We uncovered five additional miRNAs (miR-26a, miR-99b, miR-193, miR-199a-5p, and miR-218) that silenced ESC self-renewal in the absence of other miRNAs, all of which were antagonized by miR-294 and miR-302. Four of the six differentiation-inducing miRNAs induced an Rb-dependent G1 accumulation. However, all six still silenced self-renewal in the absence of the Rb proteins. These results show that the miR-294/miR-302 family acts through Rb-dependent and -independent pathways to regulate the G1 restriction point and the silencing of self-renewal, respectively.

Cell cycle regulation by microRNAs in stem cells.

The ability to self-renew and to differentiate into at least one-cell lineage defines a stem cell. Self-renewal is a process by which stem cells proliferate without differentiation. Proliferation is achieved through a series of highly regulated events of the cell cycle. MicroRNAs (miRNAs) are a class of short noncoding RNAs whose importance in these events is becoming increasingly appreciated. In this chapter, we discuss the role of miRNAs in regulating the cell cycle in various stem cells with a focus on embryonic stem cells. We also present the evidence indicating that cell cycle-regulating miRNAs are incorporated into a large regulatory network to control the self-renewal of stem cells by inducing or inhibiting differentiation. In addition, we discuss the function of cell cycle-regulating miRNAs in cancer.