Enhanced Preprints

Functional characterization of the disease-associated CCL2 rs1024611G-rs13900T haplotype: The role of the RNA-binding protein HuR

  1. Feroz Akhtar
  2. Joselin Hernandez Ruiz
  3. Ya-Guang Liu
  4. Roy G. Resendez
  5. Denis Feliers
  6. Liza D. Morales
  7. Alvaro Diaz-Badillo
  8. Donna M. Lehman
  9. Rector Arya
  10. Juan Carlos Lopez-Alvarenga
  11. John Blangero
  12. Ravindranath Duggirala
  13. Srinivas Mummidi author has email address
  1. Department of Health and Behavioral Sciences, Texas A&M University-San Antonio, Texas, USA
  2. Utah Center for Genetic Discovery, Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA
  3. Department of Pathology, School of Medicine, University of Texas Health San Antonio, San Antonio, Texas, USA
  4. Department of Medicine, School of Medicine, University of Texas Health San Antonio, San Antonio, Texas, USA
  5. South Texas Diabetes and Obesity Institute, Department of Genetics, School of Medicine, University of Texas Rio Grane Valley, Brownsville, USA
  6. Department of Population Health and Biostatistics, School of Medicine, University of Texas Rio Grande Valley, Harlingen, Texas, USA

Peer review process

Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, and public reviews.

Read more about eLife’s peer review process.

Editors

  • Reviewing Editor
    Mauro Teixeira
    Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
  • Senior Editor
    Detlef Weigel
    Max Planck Institute for Biology Tübingen, Tübingen, Germany

Reviewer #1 (Public Review):

Summary:
This paper presents evidence that a relatively common genetic variant tied to several disease phenotypes affects the interaction between the mRNA of CCL2 and the RNA binding protein HuR. CCL2 is an immune cell chemoattractant protein.

Strengths:
The study is well conducted with relevant controls. The techniques are appropriate, and several approaches provided concordant results that were generally supportive of the conclusions reached. The impact of this work, identifying a genetic variant that works by altering the binding of an RNA-regulatory protein, has important implications given that the HuR protein could be a drug target to improve its function and override this genetic change. This could have important implications for a number of diseases where this genetic variant contributes to disease risk.

Weaknesses:
The authors need to do a better job of citing prior work. Certain details of the experimental protocols need to be further elaborated or clarified to contextualize the significance of the findings, Some of the findings need to be better described.

Reviewer #2 (Public Review):

This study focuses on the differential binding of the RNA-binding protein HuR to CCL2 transcript (genetic variants rs13900 T or C). The study explores how this interaction influences the stability and translation of CCL2 mRNA. Employing a combination of bioinformatics, reporter assays, binding assays, and modulation of HuR expression, the study proposes that the rs13900T allele confers increased binding to HuR, leading to greater mRNA stability and higher translational efficiency. These findings indicate that rs13900T allele might contribute to heightened disease susceptibility due to enhanced CCL2 expression mediated by HuR. The study is interesting but needs appropriate experimental design and further strengthening. In its current form, the study suffers from several critical issues, including inadequate experimental design and the absence of control groups in key experiments.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation