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Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery
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Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery
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Journal Article
Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery
2022
Overview
Despite strong evidence that human genetic variants affect the expression of many key transcription factors involved in autoimmune diseases, establishing biological links between non-coding risk variants and the gene targets they regulate remains a considerable challenge. Here, we combine genetic, epigenomic, and CRISPR activation approaches to screen for functional variants that regulate
IRF8
expression. We demonstrate that the locus containing rs2280381 is a cell-type-specific enhancer for
IRF8
that spatially interacts with the
IRF8
promoter. Further, rs2280381 mediates
IRF8
expression through enhancer RNA AC092723.1, which recruits TET1 to the
IRF8
promoter regulating
IRF8
expression by affecting methylation levels. The alleles of rs2280381 modulate PU.1 binding and chromatin state to regulate AC092723.1 and
IRF8
expression differentially. Our work illustrates an integrative strategy to define functional genetic variants that regulate the expression of critical genes in autoimmune diseases and decipher the mechanisms underlying the dysregulation of
IRF8
expression mediated by lupus risk variants.
The functional effects of genetic loci associated with autoimmune disease are not well understood. By dissecting an autoimmune disease genetic locus, the authors define an immune cell-type-specific enhancer and the molecular mechanisms underlying the dysregulation of IRF8 expression by lupus risk variants.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 49/39
/ 49/47
/ 49/91
/ Autoimmune Diseases - genetics
/ CRISPR
/ Humanities and Social Sciences
/ Humans
/ Interferon Regulatory Factors - genetics
/ Interferon Regulatory Factors - metabolism
/ Lupus
/ Mixed Function Oxygenases - metabolism
/ Proto-Oncogene Proteins - metabolism
/ Regulatory Sequences, Nucleic Acid
/ Risk
/ RNA, Long Noncoding - genetics
/ RNA, Long Noncoding - metabolism
/ Science
