Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2020

Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma

(1) , (1) , (1) , (2) , (3) , (1) , (1) , (1) , (1) , (2) , (3) , (1) , (1) , (4) , (5) , (6) , (7) , (1) , (8) , (4) , (5) , (9) , (5) , (1) , (3) , (2) , (1)
1
2
3
4
5
6
7
8
9
John Taylor
Mark M Iles
  • Function : Author

Abstract

Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAFV600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.
Fichier principal
Vignette du fichier
s41467-020-16590-1.pdf (1.92 Mo) Télécharger le fichier
Origin : Publication funded by an institution
Loading...

Dates and versions

inserm-02879275 , version 1 (23-06-2020)

Identifiers

Cite

Jiyeon Choi, Tongwu Zhang, Andrew Vu, Julien Ablain, Matthew M Makowski, et al.. Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma. Nature Communications, 2020, 11 (1), pp.2718. ⟨10.1038/s41467-020-16590-1⟩. ⟨inserm-02879275⟩
41 View
42 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More