Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling

Brumbaugh, Justin; Stefano, Bruno Di; Wang, Xiuye; Borkent, Marti; Forouzmand, Elmira; Clowers, Katie J.; Ji, Fei; Schwarz, Benjamin A.; Kalocsay, Marian; Elledge, Stephen J.; Chen, Yue; Sadreyev, Ruslan I.; Gygi, Steven P.; Hu, Guoqing; Shi, Yongsheng; Hochedlinger, Konrad

doi:10.1016/j.cell.2017.12.035

Cited by 60 publications

(58 citation statements)

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“…In the present study, CFIm25 expression was downregulated in fibrotic skin, and this downregulation was mainly observed in (myo)fibroblasts, the key cells producing excessive ECM in skin fibrosis, suggesting that CFIm25 and APA are linked to the pathogenesis of skin fibrosis. Indeed, skin fibroblasts with CFIm25 KD have increased collagen CFIm25-mediated suppression of gene expression is mainly performed through a widespread distal-to-proximal switch of PASs (Brumbaugh et al, 2018;Kubo et al, 2006;Masamha et al, 2014). Consistent with findings in other cell types (Brumbaugh et al, 2018;Masamha et al, 2014;Sun et al, 2017), we demonstrated for the first time using a global, unbiased RNA-seq approach that CFIm25 KD in dermal fibroblasts leads to 39UTR shortening in 971 transcripts and 39UTR lengthening in only 93 transcripts.…”

Section: Discussionsupporting

confidence: 87%

Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation

Weng

Huang

Wagner

et al. 2019

Journal of Experimental Medicine

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Systemic sclerosis (SSc; scleroderma) is a multisystem fibrotic disease. The mammalian cleavage factor I 25-kD subunit (CFIm25; encoded by NUDT21) is a key regulator of alternative polyadenylation, and its depletion causes predominantly 3′UTR shortening through loss of stimulation of distal polyadenylation sites. A shortened 3′UTR will often lack microRNA target sites, resulting in increased mRNA translation due to evasion of microRNA-mediated repression. Herein, we report that CFlm25 is downregulated in SSc skin, primary dermal fibroblasts, and two murine models of dermal fibrosis. Knockdown of CFIm25 in normal skin fibroblasts is sufficient to promote the 3′UTR shortening of key TGFβ-regulated fibrotic genes and enhance their protein expression. Moreover, several of these fibrotic transcripts show 3′UTR shortening in SSc skin. Finally, mice with CFIm25 deletion in fibroblasts show exaggerated skin fibrosis upon bleomycin treatment, and CFIm25 restoration attenuates bleomycin-induced skin fibrosis. Overall, our data link this novel RNA-processing mechanism to dermal fibrosis and SSc pathogenesis.

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Section: Discussionsupporting

confidence: 87%

Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation

Weng

Huang

Wagner

et al. 2019

Journal of Experimental Medicine

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“…However, its roles in early embryogenesis are unclear. CG3689 is the fly ortholog of mammalian NUDT21, which is an RNA processing factor that regulates differential mRNA polyadenylation in differentiating stem cells (Brumbaugh et al 2018, Dettwiler et al 2004, Rüegsegger et al 1998, Yang et al 2010). The function of CG3689 in Drosophila is yet unknown beyond our finding that it is required maternally for mitotic spindle organization in the early embryo.…”

Section: Resultsmentioning

confidence: 99%

Maternal Proteins That Are Phosphoregulated upon Egg Activation Include Crucial Factors for Oogenesis, Egg Activation and Embryogenesis inDrosophila melanogaster

Zhang

Krauchunas²,

Huang

et al. 2018

G3 Genes|Genomes|Genetics

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Egg activation is essential for the successful transition from a mature oocyte to a developmentally competent egg. It consists of a series of events including the resumption and completion of meiosis, initiation of translation of some maternal mRNAs and destruction of others, and changes to the vitelline envelope. This major change of cell state is accompanied by large scale alteration in the oocyte’s phosphoproteome. We hypothesize that the cohort of proteins that are subject to phosphoregulation during egg activation are functionally important for processes before, during, or soon after this transition, potentially uniquely or as proteins carrying out essential cellular functions like those they do in other (somatic) cells. In this study, we used germline-specific RNAi to examine the function of 189 maternal proteins that are phosphoregulated during egg activation in Drosophila melanogaster. We identified 53 genes whose knockdown reduced or abolished egg production and caused a range of defects in ovarian morphology, as well as 51 genes whose knockdown led to significant impairment or abolishment of the egg hatchability. We observed different stages of developmental arrest in the embryos and various defects in spindle morphology and aberrant centrosome activities in the early arrested embryos. Our results, validated by the detection of multiple genes with previously-documented maternal effect phenotypes among the proteins we tested, revealed 15 genes with newly discovered roles in egg activation and early embryogenesis in Drosophila. Given that protein phosphoregulation is a conserved characteristic of this developmental transition, we suggest that the phosphoregulated proteins may provide a rich pool of candidates for the identification of important players in the egg-to-embryo transition.

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“…A change in 3 ′ UTR isoform ratio can be achieved through exposure of the cells to extracellular stimuli and can be mimicked experimentally by the addition of growth factors, cytokines, or neurotransmitters (Flavell et al 2008;Sandberg et al 2008;Rhinn et al 2012;Gruber et al 2014;Jia et al 2017). Expression ratios of alternative 3 ′ UTRs also change during normal development and differentiation (Lackford et al 2014;Brumbaugh et al 2018;Freimer et al 2018) as well as in disease (Mayr and Bartel 2009;Rhinn et al 2012;Batra et al 2014;Masamha et al 2014). A dramatic change in 3 ′ UTR length was recently found during mouse oocyte maturation from the germinal vesicle stage to metaphase II, which takes 9 hours and results in substantial lengthening of 3 ′ UTRs (Freimer et al 2018).…”

Section: Alternative 3 ′ Utr Isoform Ratios Are Cell Type-specific Anmentioning

confidence: 99%

“…A dramatic change in 3 ′ UTR length was recently found during mouse oocyte maturation from the germinal vesicle stage to metaphase II, which takes 9 hours and results in substantial lengthening of 3 ′ UTRs (Freimer et al 2018). For ∼20% of genes, the functional consequence of changes in alternative 3 ′ UTR isoform expression is a difference in protein levels, as the availability of binding sites of miRNAs and RBPs is altered (Gupta et al 2014;Nam et al 2014;Brumbaugh et al 2018).…”

Section: Alternative 3 ′ Utr Isoform Ratios Are Cell Type-specific Anmentioning

confidence: 99%

What Are 3′ UTRs Doing?

Mayr

2018

Cold Spring Harb Perspect Biol

372

278

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SUMMARY3' untranslated regions (3' UTRs) of messenger RNAs (mRNAs) are best known to regulate mRNA-based processes, such as mRNA localization, mRNA stability, and translation. In addition, 3' UTRs can establish 3' UTR-mediated protein-protein interactions (PPIs), and thus can transmit genetic information encoded in 3' UTRs to proteins. This function has been shown to regulate diverse protein features, including protein complex formation or posttranslational modifications, but is also expected to alter protein conformations. Therefore, 3' UTR-mediated information transfer can regulate protein features that are not encoded in the amino acid sequence. This review summarizes both 3' UTR functions-the regulation of mRNA and protein-based processes-and highlights how each 3' UTR function was discovered with a focus on experimental approaches used and the concepts that were learned. This review also discusses novel approaches to study 3' UTR functions in the future by taking advantage of recent advances in technology.

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Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling

Abstract: Due to a production error, the original publication of this article included typographic errors in Figure 1. In that figure, four instances of ''THY-1'' appeared as ''HY-1''. These errors have been corrected in print and online, and we apologize for any inconvenience.

Cited by 60 publications

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Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation

Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation

Maternal Proteins That Are Phosphoregulated upon Egg Activation Include Crucial Factors for Oogenesis, Egg Activation and Embryogenesis inDrosophila melanogaster

What Are 3′ UTRs Doing?

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