Let-7 represses <i>Nr6a1</i> and a mid-gestation developmental program in adult fibroblasts

Gurtan, Allan M.; Ravi, Arvind; Rahl, Peter B.; Bosson, Andrew; JnBaptiste, Courtney K.; Bhutkar, Arjun; Whittaker, Charles A.; Young, Richard A.; Sharp, Phillip A.

doi:10.1101/gad.215376.113

Cited by 47 publications

(61 citation statements)

References 70 publications

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“…Overexpression of one of these miRNAs, Let-7a, in mouse embryos prevents implantation (Liu et al, 2012). Targets of Let-7a include several genes that regulate cell proliferation (Gurtan et al, 2013), consistent with the view that there is depletion of specific elements required for progression beyond the blastocyst stage.…”

Section: Rodent Facultative Modelmentioning

confidence: 73%

Embryonic diapause: development on hold

Fenelon

Banerjee²,

Murphy³

2014

Int. J. Dev. Biol.

117

130

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Embryonic diapause, the temporary suspension of development of the embryo, is a fascinating reproductive strategy that has been frequently exploited across the animal kingdom. It is characterized by an arrest in development that occurs at the blastocyst stage in over 130 species of mammals. Its presumed function is to uncouple mating from parturition, to ensure that both occur at the most propitious moment for survival of the species. Diapause can be facultative, i.e. induced by physiological conditions, or obligate, i.e. present in every gestation of a species. In the latter case, the proximal signals for regulation are related to photoperiod. Three diverse models, the mouse, the mustelid carnivores and the wallaby have been studied in detail. From these studies it can be discerned that, although the endocrine cues responsible for induction of diapause and re-initiation of development vary widely between species, there are a number of commonalities. Evidence to date indicates that the uterus exercises the proximal regulatory influence over whether an embryo enters into and when it exits from diapause. Some factors have been identified that appear crucial to this regulation, in particular, the polyamines. Recent studies indicate that diapause can be induced in species where it does not exist in nature. This suggests that the potential for diapause in mammals to be due to a single evolutionary event, to which control mechanisms adapted when the trait was beneficial to reproductive success. Further work at the molecular, cellular and organismic levels will be required before the physiological basis of diapause is resolved.

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Section: Rodent Facultative Modelmentioning

confidence: 73%

Embryonic diapause: development on hold

Fenelon

Banerjee²,

Murphy³

2014

Int. J. Dev. Biol.

117

130

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“…This highlights the complexity of regulation of systems of genes by microRNAs in relationship to cancer. For example, let-7 microRNA can act as a tumor suppressor by suppressing growth rates through repression of the RAS pathway and sets of oncofetal genes (Gurtan et al 2013), while at the same time, let-7 has oncogenic activity by promoting angiogenesis by repressing the activity of FIH1. Let-7 and miR-125 suppress FIH1, which suppresses the transcriptional activity of HIF and thus angiogenesis in response to hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Global microRNA depletion suppresses tumor angiogenesis

Chen

Xue

et al. 2014

Genes Dev.

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MicroRNAs delicately regulate the balance of angiogenesis. Here we show that depletion of all microRNAs suppresses tumor angiogenesis. We generated microRNA-deficient tumors by knocking out Dicer1. These tumors are highly hypoxic but poorly vascularized, suggestive of deficient angiogenesis signaling. Expression profiling revealed that angiogenesis genes were significantly down-regulated as a result of the microRNA deficiency. Factor inhibiting hypoxia-inducible factor 1 (HIF-1), FIH1, is derepressed under these conditions and suppresses HIF transcription. Knocking out FIH1 using CRISPR/Cas9-mediated genome engineering reversed the phenotypes of microRNA-deficient cells in HIF transcriptional activity, VEGF production, tumor hypoxia, and tumor angiogenesis. Using multiplexed CRISPR/Cas9, we deleted regions in FIH1 39 untranslated regions (UTRs) that contain microRNA-binding sites, which derepresses FIH1 protein and represses hypoxia response. These data suggest that microRNAs promote tumor responses to hypoxia and angiogenesis by repressing FIH1.

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“…When miRNAs regulate transcription factors, they can affect cellular phenotype, as demonstrated by miR-134 regulation of differentiation through interactions with mRNAs encoding Nanog and LRH1 transcription factors (Tay et al, 2008), let-7 regulation of HMGA2 (Mayr et al, 2007) or miR-145 regulation of SOX9 (Rani et al, 2013). Some studies have suggested that miRNAs preferentially target transcription factors (Lewis et al, 2003) and cause widespread changes in transcriptional activation (Gurtan et al, 2013). Additionally, miRNAs are often found within network motifs containing transcription factors, suggesting that they act alongside transcription factors to buffer gene expression (Gerstein et al, 2012; Shalgi et al, 2007; Tsang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-transcriptional, and Histone Modification Measurements

et al. 2016

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Summary MicroRNAs (miRNAs) regulate diverse biological processes by repressing mRNAs, but their modest effects on direct targets, together with their participation in larger regulatory networks, make it challenging to delineate miRNA-mediated effects. Here, we describe an approach to characterizing miRNA-regulatory networks by systematically profiling transcriptional, post-transcriptional and epigenetic activity in a pair of isogenic murine fibroblast cell lines with and without Dicer expression. By RNA sequencing (RNA-seq) and CLIP (crosslinking followed by immunoprecipitation) sequencing (CLIP-seq), we found that most of the changes induced by global miRNA loss occur at the level of transcription. We then introduced a network modeling approach that integrated these data with epigenetic data to identify specific miRNA-regulated transcription factors that explain the impact of miRNA perturbation on gene expression. In total, we demonstrate that combining multiple genome-wide datasets spanning diverse regulatory modes enables accurate delineation of the downstream miRNA-regulated transcriptional network and establishes a model for studying similar networks in other systems.

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Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts

Cited by 47 publications

References 70 publications

Embryonic diapause: development on hold

Embryonic diapause: development on hold

Global microRNA depletion suppresses tumor angiogenesis

Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-transcriptional, and Histone Modification Measurements

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