Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation

Weng, Tingting; Ko, Junsuk; Masamha, Chioniso Patience; Xia, Zheng; Yu, Xiang; Chen, Ning Yuan; Molina, Jose G.; Collum, Scott D.; Mertens, Tinne; Luo, Fayong; Philip, Kemly; Davies, Jonathan; Huang, Jingjing; Wilson, Cory; Thandavarayan, Rajarajan Amirthalingam; Bruckner, Brian A.; Jyothula, Soma; Volcik, Kelly A.; Li, Lei; Han, Leng; Li, Wei; Assassi, Shervin; Karmouty‐Quintana, Harry; Wagner, Eric J.; Blackburn, Michael R.

doi:10.1172/jci122106

Cited by 48 publications

(61 citation statements)

References 57 publications

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“…Our findings indicate that mechanical cues derived from the stiffened fibrotic matrix instigate type I collagen biogenesis by selectively targeting mRNA transcripts for 3′ UTR shortening. The present study expanded the findings of a recent report on CFIm25 in the regulation of lung fibrogenesis (26). It highlighted a pivotal role of the CFIm68/CFIm25 complex in stiff matrix-induced APA and augmentation of COL1A1 expression, uncovering a potentially novel mechanism for the regulation of CFIm expression by mechanical signals derived from the ECM under fibrotic conditions.…”

Section: Discussionsupporting

confidence: 80%

“…It highlighted a pivotal role of the CFIm68/CFIm25 complex in stiff matrix-induced APA and augmentation of COL1A1 expression, uncovering a potentially novel mechanism for the regulation of CFIm expression by mechanical signals derived from the ECM under fibrotic conditions. As demonstrated in this and other studies (26), the APA events can most likely play significant roles in regulating the pathogenesis of lung fibrosis.…”

Section: Discussionsupporting

confidence: 75%

“…Dysregulation of APA has been found in multiple disease states, including oncological, immunological, and neurological diseases (25). A recent study has focused on the potential role of the CFIm25 subunit in lung fibrogenesis (26). The authors showed that CFIm25 expression was selectively reduced in α-smooth muscle actin + (α-SMA + ) fibroblasts in the lungs of patients with IPF as well as in bleomycin injury-induced experimental lung fibrosis in mice (26).…”

Section: Introductionmentioning

confidence: 99%

“…A recent study has focused on the potential role of the CFIm25 subunit in lung fibrogenesis (26). The authors showed that CFIm25 expression was selectively reduced in α-smooth muscle actin + (α-SMA + ) fibroblasts in the lungs of patients with IPF as well as in bleomycin injury-induced experimental lung fibrosis in mice (26). Overexpression of CFIm25 inhibited expression of key profibrotic factors in human IPF fibroblasts, whereas selective knockout of CFIm25 in (myo)fibroblasts augmented bleomycin-induced mouse lung fibrosis (26).…”

Section: Introductionmentioning

confidence: 99%

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Stiff matrix instigates type I collagen biogenesis by mammalian cleavage factor I complex-mediated alternative polyadenylation

Zhou¹,

Qu²,

He³

et al. 2020

JCI Insight

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stiff matrix instigates type I collagen biogenesis by mammalian cleavage factor I complex-mediated alternative polyadenylation

Zhou¹,

Qu²,

He³

et al. 2020

JCI Insight

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“…The Baylor College of Medicine Institutional Animal Care and Use Committee approved all mouse care and manipulation (IACUC, protocol AN-1013). We generated C57BL/6J Nudt21 flox/flox mice by inserting loxP sites flanking exons 2 and 3 of Nudt21 by homologous recombination in embryonic stem cells (Ozgene) (Weng et al, 2019). We then crossed male Nudt21 flox/flox mice with female C57BL/6J Sox2 -Cre hemizygous mice to obtain Nudt21 +/- mice.…”

Section: Methodsmentioning

confidence: 99%

Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits

Alcott

Yalamanchili

et al. 2019

Preprint

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29We previously showed that NUDT21-spanning copy-number variations (CNVs) are associated 30 with intellectual disability (Gennarino et al., 2015). However, the patients' CNVs also included 31 other genes. To determine if reduced NUDT21 function alone can cause disease, we generated 32 Nudt21 +/mice to mimic the human state of decreased expression. We found that although these 33 mice have 50% reduced Nudt21 mRNA, they only have 30% less of its cognate protein, CFIm25. 34Despite this partial protein-level compensation, the Nudt21 +/mice have learning deficits and 35 cortical hyperexcitability. Further, to determine the molecular mechanism driving neural 36 dysfunction, we partially inhibited NUDT21 in human stem cell-derived neurons to reduce 37 CFIm25 by 30%. This reduction in CFIm25 was sufficient to induce misregulated alternative 38 polyadenylation (APA) and protein levels in hundreds of genes, dozens of which cause 39 intellectual disability when mutated. Altogether, these results indicate that disruption of 40

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Molecular Quantitative Trait Locus Mapping in Human Complex Diseases

et al. 2022

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Mapping quantitative trait loci (QTLs) for molecular traits from chromatin to metabolites (i.e., xQTLs) provides insight into the locations and effect modes of genetic variants that influence these molecular phenotypes and the propagation of functional consequences of each variant. xQTL studies indirectly interrogate the functional landscape of the molecular basis of complex diseases, including the impact of non‐coding regulatory variants, the tissue specificity of regulatory elements, and their contribution to disease by integrating with genome‐wide association studies (GWAS). We summarize a variety of molecular xQTL studies in human tissues and cells. In addition, using the Alzheimer's Disease Sequencing Project (ADSP) as an example, we describe the ADSP xQTL project, a collaborative effort across the ADSP Functional Genomics Consortium (ADSP‐FGC). The project's ultimate goal is a reference map of Alzheimer's‐related QTLs using existing datasets from multiple omics layers to help us study the consequences of genetic variants identified in the ADSP. xQTL studies enable the identification of the causal genes and pathways in GWAS loci, which will likely aid in the discovery of novel biomarkers and therapeutic targets for complex diseases. © 2022 Wiley Periodicals LLC.

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Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation

Cited by 48 publications

References 57 publications

Stiff matrix instigates type I collagen biogenesis by mammalian cleavage factor I complex-mediated alternative polyadenylation

Stiff matrix instigates type I collagen biogenesis by mammalian cleavage factor I complex-mediated alternative polyadenylation

Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits

Molecular Quantitative Trait Locus Mapping in Human Complex Diseases

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