Abstract
Wnt/β-catenin signaling is required for embryonic dermal fibroblast cell fate, and dysregulation of this pathway is sufficient to promote fibrosis in adult tissue. The downstream modulators of Wnt/β-catenin signaling required for controlling cell fate and dermal fibrosis remain poorly understood. The discovery of regulatory long non-coding RNAs (lncRNAs) and their pivotal roles as key modulators of gene expression downstream of signaling cascades in various contexts prompted us to investigate their roles in Wnt/β-catenin signaling. Here, we have identified lncRNAs and protein-coding RNAs that are induced by β-catenin activity in mouse dermal fibroblasts using next generation RNA-sequencing. The differentially expressed protein-coding mRNAs are enriched for extracellular matrix proteins, glycoproteins, and cell adhesion, and many are also dysregulated in human fibrotic tissues. We identified 111 lncRNAs that are differentially expressed in response to activation of Wnt/β-catenin signaling. To further characterize the role of mouse lncRNAs in this pathway, we validated two novel Wnt signaling- Induced Non-Coding RNA (Wincr) transcripts referred to as Wincr1 and Wincr2. These two lncRNAs are highly expressed in mouse embryonic skin and perinatal dermal fibroblasts. Furthermore, we found that Wincr1 expression levels in perinatal dermal fibroblasts affects the expression of key markers of fibrosis (e.g., Col1a1 and Mmp10), enhances collagen contraction, and attenuates collective cell migration. Our results show that β-catenin signaling-responsive lncRNAs may modulate dermal fibroblast behavior and collagen accumulation in dermal fibrosis, providing new mechanistic insights and nodes for therapeutic intervention.
Highlights
We isolated total RNA and performed expression profiling on control and Gain of Function (GOF) neonatal dermal fibroblasts (n = 3) by whole-genome RNA-sequencing at 72 h post Adenovirus Cre (Ad-Cre) infection
These findings demonstrate that Wnt signaling differentially regulates long noncoding RNAs (lncRNAs) as well as mRNAs in dermal fibroblasts
Long non-coding RNAs have emerged as key regulators of many cellular processes, and their dysregulation has been observed in many human diseases (Wan and Wang, 2014)
Summary
Wnt/β-catenin signaling has a diverse role in both embryonic mouse skin development and in human skin diseases such as pilomatricomas, dermal hypoplasia, and fibrosis (Wang et al, 2007; Lam and Gottardi, 2011; Hamburg and Atit, 2012; Lim and Nusse, 2012). β-catenin is a key transducer of the Wnt/β-catenin signaling pathway and a regulator of transcriptionWnt/β-catenin Signaling Responsive RNAs and Function (van Amerongen and Nusse, 2009; Schuijers et al, 2014; McCrea and Gottardi, 2016). Wnt/β-catenin signaling has a diverse role in both embryonic mouse skin development and in human skin diseases such as pilomatricomas, dermal hypoplasia, and fibrosis (Wang et al, 2007; Lam and Gottardi, 2011; Hamburg and Atit, 2012; Lim and Nusse, 2012). Cell type and context-specific target gene expression provide specificity for the diverse functions of the Wnt signaling pathway (Nakamura et al, 2009; Nusse and Clevers, 2017). Studying the various mechanisms of β-catenin-mediated gene regulation will provide new insights into how context-specific transcriptional targets are activated and repressed in skin development and disease
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