CEBPB binding at rs2643219 modulates insulin sensitivity via RASGRP1–GLUT4 axis

Yongqiang Ning; Linbu Liao; Lijun Zhang; Xiao Yang; Jie Wang; Qianwen Xie; Yihui Zhang; Rui Li; Qian Liu; Xiling Zhao; Nan Wu; Shancheng Zhao; Jiguang He; Erfei Chen; Ping Gao; Gonghong Wei; Ke Dong; Wenju Sun; Jing Ye; Jian Yan

doi:10.1016/j.gendis.2026.102042

CEBPB binding at rs2643219 modulates insulin sensitivity via RASGRP1–GLUT4 axis

Yongqiang Ning (Co-first Author), Linbu Liao (Co-first Author), Lijun Zhang (Co-first Author), Xiao Yang, Jie Wang, Qianwen Xie, Yihui Zhang, Rui Li, Qian Liu, Xiling Zhao, Nan Wu, Shancheng Zhao, Jiguang He, Erfei Chen, Ping Gao, Gonghong Wei, Ke Dong, Wenju Sun, Jing Ye^*, Jian Yan^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

Abstract

Genome-wide association studies (GWAS) face critical limitations in resolving noncoding variants with functional impacts. Here, we introduce a function-first prioritization strategy that integrates SNP-SELEX-derived transcription factor binding profiles with genetic epidemiology. Applied to type 2 diabetes in the UK Biobank (n = 480,000), this approach identified 305 risk SNPs—162 novel—with significantly enhanced heritability contribution, with 91 risk SNPs co-localizing at islet enhancers. CEBPB emerged as a master regulator. Focusing on a previously uncharacterized locus (rs2643219), we demonstrated allele-specific CEBPB binding at an intestinal enhancer regulating RASGRP1—a key effector for insulin-stimulated glucose uptake. CRISPR-mediated knockout of RASGRP1 in intestinal cells ablated GLUT4 translocation and impaired glucose homeostasis in mice. Trans-ethnic validation in a Chinese cohort (n = 1718) confirmed rs2643219's clinical relevance (OR = 1.30; P = 0.023). Our strategy bridges functional genomics with pathophysiological mechanisms, establishing a blueprint for complex disease variant prioritization. © 2026 Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.

Original language	English
Article number	102042
Journal	Genes & Diseases
Online published	17 Jan 2026
DOIs	https://doi.org/10.1016/j.gendis.2026.102042
Publication status	Online published - 17 Jan 2026

Funding

This work was supported by Shenzhen Medical Research Fund (China) (No. B2302027), the National Natural Science Foundation of China (No. 32070596, 32100468, 32270634, 82003115), Shaanxi Academy of Fundamental Sciences (Chemistry and Biology) (China) (No. 22JHZ009, 22JHQ084), Guangdong Natural Science Fund (China) (No. 2024A1515012685), China Postdoctoral Science Foundation (No. 2020M673632XB), Research Grants Council of Hong Kong, China (No. 11101022), Innovation and Technology Commission of Hong Kong, China (No. ITS/087/22), and City University of Hong Kong, China (No. 9610618, 7006043).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

CEBPB
Enhancer
RASGRP1
rs2643219
Single-nucleotide polymorphism
Type 2 diabetes

RGC Funding Information

RGC-funded

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10.1016/j.gendis.2026.102042

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1 Finished
1 Active

GRF: Unravelling the Molecular Mechanism of DNA Demethylation around CTCF Binding Sites in Mammalian Cells
YAN, J. (Principal Investigator / Project Coordinator)
1/01/23 → …
Project: Research
ITF: Developing A Method for Efficient Detection of Binding Proteins of Specific RNA in Cells and Tissues
YAN, J. (Principal Investigator / Project Coordinator) & ZHANG, L. (Co-Investigator)
1/03/24 → 31/08/25
Project: Research

Cite this

Ning, Y., Liao, L., Zhang, L., Yang, X., Wang, J., Xie, Q., Zhang, Y., Li, R., Liu, Q., Zhao, X., Wu, N., Zhao, S., He, J., Chen, E., Gao, P., Wei, G., Dong, K., Sun, W., Ye, J., & Yan, J. (2026). CEBPB binding at rs2643219 modulates insulin sensitivity via RASGRP1–GLUT4 axis. Genes & Diseases, Article 102042. Advance online publication. https://doi.org/10.1016/j.gendis.2026.102042

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title = "CEBPB binding at rs2643219 modulates insulin sensitivity via RASGRP1–GLUT4 axis",

abstract = "Genome-wide association studies (GWAS) face critical limitations in resolving noncoding variants with functional impacts. Here, we introduce a function-first prioritization strategy that integrates SNP-SELEX-derived transcription factor binding profiles with genetic epidemiology. Applied to type 2 diabetes in the UK Biobank (n = 480,000), this approach identified 305 risk SNPs—162 novel—with significantly enhanced heritability contribution, with 91 risk SNPs co-localizing at islet enhancers. CEBPB emerged as a master regulator. Focusing on a previously uncharacterized locus (rs2643219), we demonstrated allele-specific CEBPB binding at an intestinal enhancer regulating RASGRP1—a key effector for insulin-stimulated glucose uptake. CRISPR-mediated knockout of RASGRP1 in intestinal cells ablated GLUT4 translocation and impaired glucose homeostasis in mice. Trans-ethnic validation in a Chinese cohort (n = 1718) confirmed rs2643219's clinical relevance (OR = 1.30; P = 0.023). Our strategy bridges functional genomics with pathophysiological mechanisms, establishing a blueprint for complex disease variant prioritization. {\textcopyright} 2026 Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.",

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author = "Yongqiang Ning and Linbu Liao and Lijun Zhang and Xiao Yang and Jie Wang and Qianwen Xie and Yihui Zhang and Rui Li and Qian Liu and Xiling Zhao and Nan Wu and Shancheng Zhao and Jiguang He and Erfei Chen and Ping Gao and Gonghong Wei and Ke Dong and Wenju Sun and Jing Ye and Jian Yan",

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day = "17",

doi = "10.1016/j.gendis.2026.102042",

language = "English",

journal = "Genes & Diseases",

issn = "2352-3042",

publisher = "KeAi Communications",

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TY - JOUR

T1 - CEBPB binding at rs2643219 modulates insulin sensitivity via RASGRP1–GLUT4 axis

AU - Ning, Yongqiang

AU - Liao, Linbu

AU - Zhang, Lijun

AU - Yang, Xiao

AU - Wang, Jie

AU - Xie, Qianwen

AU - Zhang, Yihui

AU - Li, Rui

AU - Liu, Qian

AU - Zhao, Xiling

AU - Wu, Nan

AU - Zhao, Shancheng

AU - He, Jiguang

AU - Chen, Erfei

AU - Gao, Ping

AU - Wei, Gonghong

AU - Dong, Ke

AU - Sun, Wenju

AU - Ye, Jing

AU - Yan, Jian

PY - 2026/1/17

Y1 - 2026/1/17

N2 - Genome-wide association studies (GWAS) face critical limitations in resolving noncoding variants with functional impacts. Here, we introduce a function-first prioritization strategy that integrates SNP-SELEX-derived transcription factor binding profiles with genetic epidemiology. Applied to type 2 diabetes in the UK Biobank (n = 480,000), this approach identified 305 risk SNPs—162 novel—with significantly enhanced heritability contribution, with 91 risk SNPs co-localizing at islet enhancers. CEBPB emerged as a master regulator. Focusing on a previously uncharacterized locus (rs2643219), we demonstrated allele-specific CEBPB binding at an intestinal enhancer regulating RASGRP1—a key effector for insulin-stimulated glucose uptake. CRISPR-mediated knockout of RASGRP1 in intestinal cells ablated GLUT4 translocation and impaired glucose homeostasis in mice. Trans-ethnic validation in a Chinese cohort (n = 1718) confirmed rs2643219's clinical relevance (OR = 1.30; P = 0.023). Our strategy bridges functional genomics with pathophysiological mechanisms, establishing a blueprint for complex disease variant prioritization. © 2026 Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.

AB - Genome-wide association studies (GWAS) face critical limitations in resolving noncoding variants with functional impacts. Here, we introduce a function-first prioritization strategy that integrates SNP-SELEX-derived transcription factor binding profiles with genetic epidemiology. Applied to type 2 diabetes in the UK Biobank (n = 480,000), this approach identified 305 risk SNPs—162 novel—with significantly enhanced heritability contribution, with 91 risk SNPs co-localizing at islet enhancers. CEBPB emerged as a master regulator. Focusing on a previously uncharacterized locus (rs2643219), we demonstrated allele-specific CEBPB binding at an intestinal enhancer regulating RASGRP1—a key effector for insulin-stimulated glucose uptake. CRISPR-mediated knockout of RASGRP1 in intestinal cells ablated GLUT4 translocation and impaired glucose homeostasis in mice. Trans-ethnic validation in a Chinese cohort (n = 1718) confirmed rs2643219's clinical relevance (OR = 1.30; P = 0.023). Our strategy bridges functional genomics with pathophysiological mechanisms, establishing a blueprint for complex disease variant prioritization. © 2026 Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.

KW - CEBPB

KW - Enhancer

KW - RASGRP1

KW - rs2643219

KW - Single-nucleotide polymorphism

KW - Type 2 diabetes

U2 - 10.1016/j.gendis.2026.102042

DO - 10.1016/j.gendis.2026.102042

M3 - RGC 21 - Publication in refereed journal

SN - 2352-3042

JO - Genes & Diseases

JF - Genes & Diseases

M1 - 102042

ER -

CEBPB binding at rs2643219 modulates insulin sensitivity via RASGRP1–GLUT4 axis

Abstract

Funding

UN SDGs

Research Keywords

RGC Funding Information

Access Output

Other Access Options

Permanent Link

Fingerprint

Projects

GRF: Unravelling the Molecular Mechanism of DNA Demethylation around CTCF Binding Sites in Mammalian Cells

ITF: Developing A Method for Efficient Detection of Binding Proteins of Specific RNA in Cells and Tissues

Cite this