ORIGINAL RESEARCH article
Front. Bioinform.
Sec. Genomic Analysis
REST Missense Mutations Reveals Disrupted Re1 Motif Binding and Co-Repressor Interactions in Uterine Fibroids
Provisionally accepted
- Vellore Institute of Technology, Vellore, India
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
The Re1-Silencing Transcription Factor (REST) is a master regulator of gene silencing, orchestrating transcriptional repression by tethering chromatin-modifying co-repressors to the Re1 motif of target genes. While REST is recognized as a sentinel of cellular identity, its role in uterine fibroids (UF) remains unclear. In this study, a deep structural interrogation of REST reveals how specific missense mutations may fracture its architecture, destabilize molecular alliances, and compromise DNA-binding precision, potentially unleashing transcriptional noise that fuels fibroid growth. Through expansive in-silico analysis of 938 missense SNPs, five structurally disruptive REST variants (Y31C, Y31D, L76Q, Y283C, L427Q) were identified at evolutionarily conserved residues across ten primate species. Structural modeling and docking analyses exposed weakened affinity for co-repressors, with Y283C notably reducing SIN3A interaction (Z-score: -2.4 to -1.2) and impairing DNA binding (Z-score: -2.0 to -1.3). Molecular dynamics simulations showed that Y283C increases rigidity (RMSF: 0.33 to 0.27 nm), reduces compactness (Rg: 3.48 to 3.51 nm), and lowers potential energy. Upon Re1 binding, destabilization intensified, with RMSD rising (0.95 to 1.07 nm) and energy shifting markedly. This integrative analysis points to REST as a candidate regulatory component in fibroid biology, where its perturbation may be associated with altered transcriptional control and could inform future strategies to investigate dysregulation in this disease.
Keywords: MD simulations, Protein- protein docking, Protein-DNA docking, Re1 motif, REST (Re1-Silencing Transcription Factor), Uterine fibroids
Received: 11 Sep 2025; Accepted: 10 Dec 2025.
Copyright: © 2025 Sriram, Palanichamy, Subash, Gupta and C. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Sudandiradoss C
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.