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

Zhou, Zijing; Qu, Jing; He, Li; Zhu, Yi; Yang, Shanzhong; Zhang, Feng; Guo, Tao; Peng, Hong; Chen, Ping; Zhou, Yong

doi:10.1172/jci.insight.133972

Cited by 22 publications

(17 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…APS is one of the most important post-transcriptional regulatory mechanisms involved in mRNA metabolism modulation, and its dysregulation has been implicated in many disease states [315][316][317]. A number of studies have reported a link between APA and fibrotic conditions including IPF [318][319][320][321]. Recently, Zhou et al reported that matrix stiffness induces cell fibrotic responses by a signaling mechanism involving the modulation of APA by the mammalian cleavage factor I (CFIm) [318].…”

Section: Alternative Polyadenylationmentioning

confidence: 99%

“…A number of studies have reported a link between APA and fibrotic conditions including IPF [318][319][320][321]. Recently, Zhou et al reported that matrix stiffness induces cell fibrotic responses by a signaling mechanism involving the modulation of APA by the mammalian cleavage factor I (CFIm) [318]. These authors demonstrated that a stiff matrix acts as a down-regulator of the CFIm subunits CFIm68, CFIm59 and CFIm25, promoting the APA-dependent up regulation of collagen and fibronectin production in primary human lung fibroblasts [318].…”

Section: Alternative Polyadenylationmentioning

confidence: 99%

“…Recently, Zhou et al reported that matrix stiffness induces cell fibrotic responses by a signaling mechanism involving the modulation of APA by the mammalian cleavage factor I (CFIm) [318]. These authors demonstrated that a stiff matrix acts as a down-regulator of the CFIm subunits CFIm68, CFIm59 and CFIm25, promoting the APA-dependent up regulation of collagen and fibronectin production in primary human lung fibroblasts [318]. In vivo experiments have also reported a strong association between matrix stiffness and CFIm subunits in a bleomycin-induced mouse model of pulmonary fibrosis [318].…”

Section: Alternative Polyadenylationmentioning

confidence: 99%

“…These authors demonstrated that a stiff matrix acts as a down-regulator of the CFIm subunits CFIm68, CFIm59 and CFIm25, promoting the APA-dependent up regulation of collagen and fibronectin production in primary human lung fibroblasts [318]. In vivo experiments have also reported a strong association between matrix stiffness and CFIm subunits in a bleomycin-induced mouse model of pulmonary fibrosis [318]. By regulating APA, the CFIm subunit CFIm25 appears to play an essential role in fibroblast-to-myofibroblast differentiation [321].…”

Section: Alternative Polyadenylationmentioning

confidence: 99%

See 3 more Smart Citations

Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

Phan

Paliogiannis

Nasrallah

et al. 2020

Cell. Mol. Life Sci.

239

152

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, and typically lethal disease characterized by an abnormal fibrotic response involving vast areas of the lungs. Given the poor knowledge of the mechanisms underpinning IPF onset and progression, a better understanding of the cellular processes and molecular pathways involved is essential for the development of effective therapies, currently lacking. Besides a number of established IPF-associated risk factors, such as cigarette smoking, environmental factors, comorbidities, and viral infections, several other processes have been linked with this devastating disease. Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling. Moreover, molecules, such as chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, non-coding RNAs, and cellular processes including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia, and alternative polyadenylation have been linked with IPF development. Importantly, strategies targeting these processes have been investigated to modulate abnormal cellular phenotypes and maintain tissue homeostasis in the lung. This review provides an update regarding the emerging cellular and molecular mechanisms involved in the onset and progression of IPF.

show abstract

Section: Alternative Polyadenylationmentioning

confidence: 99%

Section: Alternative Polyadenylationmentioning

confidence: 99%

Section: Alternative Polyadenylationmentioning

confidence: 99%

Section: Alternative Polyadenylationmentioning

confidence: 99%

See 2 more Smart Citations

Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

Phan

Paliogiannis

Nasrallah

et al. 2020

Cell. Mol. Life Sci.

239

152

View full text Add to dashboard Cite

show abstract

“…Matrix stiffening is a prominent feature of lung fibrosis ( Booth et al, 2012 ; Liu et al, 2010 ; Zhou et al, 2020 ). The formation of intra- and intermolecular cross-links in the extracellular matrix (ECM), in particular collagenous ECM, by enzyme- and non-enzyme-mediated cross-linking reactions is a crucial factor that stiffens the ECM ( Barry-Hamilton et al, 2010 ; Greenwald, 2007 ; Olsen et al, 2011 ; Simm, 2013 ; Verzijl et al, 2002 ; Wells, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice

Yang

Zhu

et al. 2021

Journal of Experimental Medicine

Self Cite

View full text Add to dashboard Cite

Aging is a strong risk factor and an independent prognostic factor for progressive human idiopathic pulmonary fibrosis (IPF). Aged mice develop nonresolving pulmonary fibrosis following lung injury. In this study, we found that mouse double minute 4 homolog (MDM4) is highly expressed in the fibrotic lesions of human IPF and experimental pulmonary fibrosis in aged mice. We identified MDM4 as a matrix stiffness–regulated endogenous inhibitor of p53. Reducing matrix stiffness down-regulates MDM4 expression, resulting in p53 activation in primary lung myofibroblasts isolated from IPF patients. Gain of p53 function activates a gene program that sensitizes lung myofibroblasts to apoptosis and promotes the clearance of apoptotic myofibroblasts by macrophages. Destiffening of the fibrotic lung matrix by targeting nonenzymatic cross-linking or genetic ablation of Mdm4 in lung (myo)fibroblasts activates the Mdm4–p53 pathway and promotes lung fibrosis resolution in aged mice. These findings suggest that mechanosensitive MDM4 is a molecular target with promising therapeutic potential against persistent lung fibrosis associated with aging.

show abstract

An AluYa5 Insertion in the 3′UTR of COL4A1 and Cerebral Small Vessel Disease

Aloui,

Neumann,

Bergametti

et al. 2024

JAMA Netw Open

View full text Add to dashboard Cite

ImportanceCerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes.ObjectiveTo identify novel genes and mechanisms associated with familial CSVD.Design, Setting, and ParticipantsThis 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset &lt;age 55 years and ≥1 first-degree relative with CSVD) were referred to the French cerebrovascular referral center between 2013 and 2023. The large-scale gnomAD structural variant database and 467 healthy individuals of French ancestry were used as a control group.Main Outcomes and MeasuresA pathogenic AluYa5 insertion was identified within the COL4A1 3′UTR in the 2 large families with CSVD. Reverse transcriptase–quantitative polymerase chain reaction (RT-qPCR), Western blot, and long-read RNA sequencing were used to investigate outcomes associated with the insertion using patient fibroblasts. Clinical and magnetic resonance imaging features of probands with variants and available relatives were assessed.ResultsAmong 246 probands (141 females [57.3%]; median [IQR] age at referral, 56 [49-64] years), 7 patients of French ancestry carried the insertion. This insertion was absent in 467 healthy French individuals in a control group (odds ratio, ∞; 95% CI, 2.78 to ∞; P = 5 × 10−4) and 10 847 individuals from the gnomAD structural variant database (odds ratio, ∞; 95% CI, 64.77 to ∞; P = 2.42 × 10−12). In these 7 patients’ families, 19 family members with CSVD carried the insertion. RT-qPCR and Western blot showed an upregulation of COL4A1 mRNA (10.6-fold increase; 95% CI, 1.4-fold to 17.1-fold increase) and protein levels (2.8-fold increase; 95% CI, 2.1-fold to 3.5-fold increase) in patient vs control group fibroblasts. Long-read RNA sequencing data showed that the insertion was associated with perturbation in the use of canonical COL4A1 polyadenylation signals (approximately 87% of isoforms transcribed from the wild type allele vs 5% of isoforms transcribed from the allele with the insertion used the 2 distal canonical polyadenylation signals). The main clinical feature of individuals with CSVD was the recurrence of pontine ischemic lesions starting at an early age (17 of 19 patients [89.5%]).Conclusions and relevanceThis study found a novel mechanism associated with COL4A1 upregulation and a highly penetrant adult-onset CSVD. These findings suggest that quantitative alterations of the cerebrovascular matrisome are associated with CSVD pathogenesis, with diagnostic and therapeutic implications.

show abstract

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

Cited by 22 publications

References 48 publications

Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice

An AluYa5 Insertion in the 3′UTR of COL4A1 and Cerebral Small Vessel Disease

Contact Info

Product

Resources

About