Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency - 05/06/24

Doi : 10.1016/j.jaci.2023.12.023

Xubo Huang, MD, MS ^a,^{^{∗
These authors contributed equally to the study.}}, Jinxia Huang, MD, MS ^a,^{^{∗
These authors contributed equally to the study.},}^{^{‡
Present address: Foresea Life Insurance Guangzhou General Hospital, Guangzhou, China.}}, Xiumei Li, MS ^b,^{^{∗
These authors contributed equally to the study.}}, Jingxian Fan, MS ^b,^g, Desheng Zhou, MD, MS ^a, Hui-Qi Qu, MD, PhD ^c, Joseph T. Glessner, PhD ^c,^k,^l, Dandan Ji, MS ^b, Qi Jia, PhD ^d, Zhiyong Ding, PhD ^e, Nan Wang, PhD ^e, Wei Wei, MD ^f, Xing Lyu, MD ^f, Mulin Jun Li, PhD ^g, Zhe Liu, PhD ^h, Wei Liu, MD ^i,^j, Yongjie Wei, PhD ^a, Hakon Hakonarson, MD, PhD ^c,^k,^l, Qianghua Xia, PhD ^b,^g,^⁎ , Jin Li, PhD ^b,^f,^⁎
^a Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
^b Department of Cell Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Tianjin Institute of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
^g Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
^h Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
^f Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, China
ⁱ Tianjin Children’s Hospital (Tianjin University Children’s Hospital), Tianjin, China
^j Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
^c Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pa
^k Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pa
^l Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
^d International School of Information Science Engineering, Dalian University of Technology, Dalian, China
^e Mills Institute for Personalized Cancer Care, Fynn Biotechnologies Ltd, Jinan, China

^∗Corresponding author: Jin Li, PhD, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.Department of Cell Biology2011 Collaborative Innovation Center of Tianjin for Medical EpigeneticsTianjin Medical UniversityTianjin300070China^∗Qianghua Xia, PhD, Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.Department of BioinformaticsSchool of Basic Medical SciencesTianjin Medical UniversityTianjin300070China

Abstract

Background

CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID).

Objectives

This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID.

Methods

The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array.

Results

This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4⁺ T cells to immune stimulation.

Conclusions

Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

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Key words : AKT, autoimmunity, chromatin interaction, CLEC16A, common variable immunodeficiency disorder, primary immunodeficiency

Abbreviations used : CHOP, CVID, DEG, FC, GWAS, KO, MS, PIDD, PMA, RA, RNA-seq, SILAC

Plan

Methods

Results

SNP rs11642009 is associated with several autoimmune disorders and is a candidate functional variant for CVID

The genomic region harboring rs11642009 regulates the expression of multiple genes

SNP rs11642009 interacts with the regulatory region of multiple genes

Distinct transcription factor complexes mediate the allele specific chromatin looping

SNP rs11642009 deletion induces potent immune signaling alteration

rs11642009 deletion induces profound changes in response to stimulation

Discussion

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Vol 153 - N° 6

P. 1668-1680 - juin 2024 Retour au numéro

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Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency - 05/06/24

Abstract

Background

Objectives

Methods

Results

Conclusions

Plan

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