TGF‐β‐induced fibrotic stress increases G‐quadruplex formation in human fibroblasts

Priyanka Toshniwal, Michelle Nguyen, Aurore Guédin , Helena Viola, Diwei Ho, Yongeun Kim, Uditi Bhatt, Charlie Bond, Livia Hool, Laurence Hurley, Jean-Louis Mergny, Mark Fear, Fiona Wood, Killugudi Swaminatha Iyer, Nicole Smith

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Scar formation after wound healing is a major medical problem. A better understanding of the dynamic nuclear architecture of the genome during wound healing could provide insights into the underlying pathophysiology and enable novel therapeutic strategies. Here, we demonstrate that TGF‐β‐ induced fibrotic stress increases formation of the dynamic secondary DNA structures called G‐quadruplexes in skin fibroblasts, which is coincident with increased expression of collagen 1. This G‐quadruplex formation is attenuated by a small molecule inhibitor of intracellular Ca2+ influx and an anti‐fibrotic compound. In addition, we identify G‐quadruplex‐forming sequences in the promoter region of COL1A1, which encodes collagen 1, and confirm their ability to form G‐quadruplex structures under physiologically relevant conditions. Our findings reveal a link between G‐quadruplexes and scar formation that may lead to novel therapeutic interventions.
Original languageEnglish
Pages (from-to)3149-3161
Number of pages13
JournalFEBS Letters
Volume593
Issue number22
DOIs
Publication statusPublished - Nov 2019

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Fibroblasts
Wound Healing
Cicatrix
Collagen
Medical problems
Genetic Promoter Regions
Skin
Genes
Genome
Molecules
DNA
Therapeutics

Cite this

Toshniwal, Priyanka ; Nguyen, Michelle ; Guédin , Aurore ; Viola, Helena ; Ho, Diwei ; Kim, Yongeun ; Bhatt, Uditi ; Bond, Charlie ; Hool, Livia ; Hurley, Laurence ; Mergny, Jean-Louis ; Fear, Mark ; Wood, Fiona ; Swaminatha Iyer, Killugudi ; Smith, Nicole. / TGF‐β‐induced fibrotic stress increases G‐quadruplex formation in human fibroblasts. In: FEBS Letters. 2019 ; Vol. 593, No. 22. pp. 3149-3161.
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abstract = "Scar formation after wound healing is a major medical problem. A better understanding of the dynamic nuclear architecture of the genome during wound healing could provide insights into the underlying pathophysiology and enable novel therapeutic strategies. Here, we demonstrate that TGF‐β‐ induced fibrotic stress increases formation of the dynamic secondary DNA structures called G‐quadruplexes in skin fibroblasts, which is coincident with increased expression of collagen 1. This G‐quadruplex formation is attenuated by a small molecule inhibitor of intracellular Ca2+ influx and an anti‐fibrotic compound. In addition, we identify G‐quadruplex‐forming sequences in the promoter region of COL1A1, which encodes collagen 1, and confirm their ability to form G‐quadruplex structures under physiologically relevant conditions. Our findings reveal a link between G‐quadruplexes and scar formation that may lead to novel therapeutic interventions.",
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TGF‐β‐induced fibrotic stress increases G‐quadruplex formation in human fibroblasts. / Toshniwal, Priyanka; Nguyen, Michelle; Guédin , Aurore ; Viola, Helena; Ho, Diwei; Kim, Yongeun; Bhatt, Uditi; Bond, Charlie; Hool, Livia; Hurley, Laurence; Mergny, Jean-Louis; Fear, Mark; Wood, Fiona; Swaminatha Iyer, Killugudi; Smith, Nicole.

In: FEBS Letters, Vol. 593, No. 22, 11.2019, p. 3149-3161.

Research output: Contribution to journalArticle

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AU - Toshniwal, Priyanka

AU - Nguyen, Michelle

AU - Guédin , Aurore

AU - Viola, Helena

AU - Ho, Diwei

AU - Kim, Yongeun

AU - Bhatt, Uditi

AU - Bond, Charlie

AU - Hool, Livia

AU - Hurley, Laurence

AU - Mergny, Jean-Louis

AU - Fear, Mark

AU - Wood, Fiona

AU - Swaminatha Iyer, Killugudi

AU - Smith, Nicole

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AB - Scar formation after wound healing is a major medical problem. A better understanding of the dynamic nuclear architecture of the genome during wound healing could provide insights into the underlying pathophysiology and enable novel therapeutic strategies. Here, we demonstrate that TGF‐β‐ induced fibrotic stress increases formation of the dynamic secondary DNA structures called G‐quadruplexes in skin fibroblasts, which is coincident with increased expression of collagen 1. This G‐quadruplex formation is attenuated by a small molecule inhibitor of intracellular Ca2+ influx and an anti‐fibrotic compound. In addition, we identify G‐quadruplex‐forming sequences in the promoter region of COL1A1, which encodes collagen 1, and confirm their ability to form G‐quadruplex structures under physiologically relevant conditions. Our findings reveal a link between G‐quadruplexes and scar formation that may lead to novel therapeutic interventions.

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