let-7 miRNAs Can Act through Notch to Regulate Human Gliogenesis

Patterson, Michaela; Gaeta, Xavier; Loo, Karen M.J. van; Edwards, Malia M.; Smale, Stephen T.; Cinkornpumin, Jessica; Xie, Yuan; Listgarten, Jennifer; Azghadi, Soheila; Douglass, Stephen M.; Pellegrini, Matteo; Lowry, William E.

doi:10.1016/j.stemcr.2014.08.015

Cited by 93 publications

(102 citation statements)

References 44 publications

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“…S13). Because let-7 is found to be highly expressed in other cell types such as late retinal progenitors and glial cells (54,55), further studies to address the mechanism by which let-7 regulates cardiac maturation would also shed light on maturation of other cells types in vitro. In conclusion, our discovery of a small RNA essential to promote cardiac maturation and metabolic transition provides a unique focus for the rational development of strategies for generating mature tissue types useful for regenerative medicine.…”

Section: Discussionmentioning

confidence: 99%

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Kuppusamy

Jones²,

Sperber

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

229

218

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In metazoans, transition from fetal to adult heart is accompanied by a switch in energy metabolism-glycolysis to fatty acid oxidation. The molecular factors regulating this metabolic switch remain largely unexplored. We first demonstrate that the molecular signatures in 1-year (y) matured human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are similar to those seen in in vivo-derived mature cardiac tissues, thus making them an excellent model to study human cardiac maturation. We further show that let-7 is the most highly up-regulated microRNA (miRNA) family during in vitro human cardiac maturation. Gain-and loss-of-function analyses of let-7g in hESC-CMs demonstrate it is both required and sufficient for maturation, but not for early differentiation of CMs. Overexpression of let-7 family members in hESC-CMs enhances cell size, sarcomere length, force of contraction, and respiratory capacity. Interestingly, large-scale expression data, target analysis, and metabolic flux assays suggest this let-7-driven CM maturation could be a result of down-regulation of the phosphoinositide 3 kinase (PI3K)/AKT protein kinase/insulin pathway and an up-regulation of fatty acid metabolism. These results indicate let-7 is an important mediator in augmenting metabolic energetics in maturing CMs. Promoting maturation of hESC-CMs with let-7 overexpression will be highly significant for basic and applied research.everal coronary heart diseases (CHDs) are characterized by cardiac dysfunctions predominantly manifested during cardiac maturation (1, 2). Dramatic changes in energy metabolism occur during this postnatal cardiac maturation (3). At early embryonic development, glycolysis is a major source of energy for cardiomyocytes (CMs) (4, 5). However, as the cardiomyocytes mature, mitochondrial oxidative metabolism increases with fatty acid oxidation, providing 90% of the heart's energy demands (6-8). This switch in cardiac metabolism has been shown to have important implications during in vivo cardiac maturation (9). In contrast to the relatively advanced knowledge of the genetic network that contributes to heart development during embryogenesis (10, 11), molecular factors that regulate peri-and postnatal cardiac maturation, particularly in relation to the metabolic switch, remain largely unclear. So far, studies to understand the transition of the glycolysisdependent fetal heart to oxidative metabolism in the adult heart have been mostly related to the peroxisome proliferatoractivated receptor (PPAR)/estrogen-related receptor/PPARγ coactivator-1α circuit (7,8,12). However, it is currently unknown what other factors act upstream or in synergy with this pathway in controlling cardiac energetics.miRNAs have emerged as key factors in controlling the complex regulatory network in a developing heart (13). Genetic studies that enrich or deplete miRNAs in specific cardiac tissue types and large-scale gene expression studies have demonstrated that they achieve such complex control at the level of cardiac gene expression (14-16). We sou...

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Section: Discussionmentioning

confidence: 99%

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Kuppusamy

Jones²,

Sperber

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

229

218

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“…MiScript primers, RNU6_2 (Qiagen), were used as housekeeping control. The expression of primary and precursor miRNA transcripts were measured using previous published primers (Patterson et al, 2014). …”

Section: Methodsmentioning

confidence: 99%

ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

et al. 2016

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SUMMARY Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1E912 mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small molecule tool compound antagonizes ADAR1’s effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSC with active JAK2 signaling.

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“…Once miR-153 levels are decreased, NFIA/B accumulates and NPCs acquire gliogenic competence (Tsuyama et al, 2015). Additional miRNAs that are important in glial cell lineage decisions include let-7 family members (Gökbuget et al, 2015;Patterson et al, 2014;Shenoy et al, 2015).…”

Section: Gliogenesismentioning

confidence: 99%

MicroRNAs in neural development: from master regulators to fine-tuners

2017

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The proper formation and function of neuronal networks is required for cognition and behavior. Indeed, pathophysiological states that disrupt neuronal networks can lead to neurodevelopmental disorders such as autism, schizophrenia or intellectual disability. It is wellestablished that transcriptional programs play major roles in neural circuit development. However, in recent years, post-transcriptional control of gene expression has emerged as an additional, and probably equally important, regulatory layer. In particular, it has been shown that microRNAs (miRNAs), an abundant class of small regulatory RNAs, can regulate neuronal circuit development, maturation and function by controlling, for example, local mRNA translation. It is also becoming clear that miRNAs are frequently dysregulated in neurodevelopmental disorders, suggesting a role for miRNAs in the etiology and/or maintenance of neurological disease states. Here, we provide an overview of the most prominent regulatory miRNAs that control neural development, highlighting how they act as 'master regulators' or 'fine-tuners' of gene expression, depending on context, to influence processes such as cell fate determination, cell migration, neuronal polarization and synapse formation.

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let-7 miRNAs Can Act through Notch to Regulate Human Gliogenesis

Cited by 93 publications

References 44 publications

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

MicroRNAs in neural development: from master regulators to fine-tuners

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