Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function
Abstract Genome wide association studies (GWAS) identify many risks for Crohn’s disease (CD), including a site near the metabolism gene laccase domain containing 1 (LACC1). We previously found this site near LACC1 was associated with decreased LACC1 expression in T lymphocytes, yet the mechanism aff...
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| Format: | Article |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57744-3 |
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| author | Yingcong Li Gabriel Ascui Martina Dicker Thomas Riffelmacher Vivek Chandra Benjamin Schmiedel Ting-Fang Chou Pandurangan Vijayanand Mitchell Kronenberg |
| author_facet | Yingcong Li Gabriel Ascui Martina Dicker Thomas Riffelmacher Vivek Chandra Benjamin Schmiedel Ting-Fang Chou Pandurangan Vijayanand Mitchell Kronenberg |
| author_sort | Yingcong Li |
| collection | DOAJ |
| description | Abstract Genome wide association studies (GWAS) identify many risks for Crohn’s disease (CD), including a site near the metabolism gene laccase domain containing 1 (LACC1). We previously found this site near LACC1 was associated with decreased LACC1 expression in T lymphocytes, yet the mechanism affecting gene expression and its links to T cell function and inflammatory disease were unknown. Here we identify variants in the promoter region that influence transcription of LACC1. Direct association of disease-risk variants with lower LACC1 pre-mRNA in human CD4+ T cells is confirmed by comparing transcripts from each allele from donors heterozygous for the LACC1 CD-risk allele. Using gene editing, we validate the function of this promoter region in LACC1 expression in T cells. Human CD4+ T cells with LACC1 gene knockdown show altered metabolism, including reduced oxygen consumption rate, and reduced in vitro regulatory T cell differentiation. Therefore, our study provides a mechanism linking these specific LACC1 variants to colitis by attributing promoter region variants to changes in T cell metabolism and function. |
| format | Article |
| id | doaj-art-7fb58bb6a26c4bd688c5a94c7344ff56 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7fb58bb6a26c4bd688c5a94c7344ff562025-08-20T02:56:09ZengNature PortfolioNature Communications2041-17232025-03-0116111610.1038/s41467-025-57744-3Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell functionYingcong Li0Gabriel Ascui1Martina Dicker2Thomas Riffelmacher3Vivek Chandra4Benjamin Schmiedel5Ting-Fang Chou6Pandurangan Vijayanand7Mitchell Kronenberg8La Jolla Institute for ImmunologyLa Jolla Institute for ImmunologyLa Jolla Institute for ImmunologyLa Jolla Institute for ImmunologyLa Jolla Institute for ImmunologyLa Jolla Institute for ImmunologyLa Jolla Institute for ImmunologyLa Jolla Institute for ImmunologyLa Jolla Institute for ImmunologyAbstract Genome wide association studies (GWAS) identify many risks for Crohn’s disease (CD), including a site near the metabolism gene laccase domain containing 1 (LACC1). We previously found this site near LACC1 was associated with decreased LACC1 expression in T lymphocytes, yet the mechanism affecting gene expression and its links to T cell function and inflammatory disease were unknown. Here we identify variants in the promoter region that influence transcription of LACC1. Direct association of disease-risk variants with lower LACC1 pre-mRNA in human CD4+ T cells is confirmed by comparing transcripts from each allele from donors heterozygous for the LACC1 CD-risk allele. Using gene editing, we validate the function of this promoter region in LACC1 expression in T cells. Human CD4+ T cells with LACC1 gene knockdown show altered metabolism, including reduced oxygen consumption rate, and reduced in vitro regulatory T cell differentiation. Therefore, our study provides a mechanism linking these specific LACC1 variants to colitis by attributing promoter region variants to changes in T cell metabolism and function.https://doi.org/10.1038/s41467-025-57744-3 |
| spellingShingle | Yingcong Li Gabriel Ascui Martina Dicker Thomas Riffelmacher Vivek Chandra Benjamin Schmiedel Ting-Fang Chou Pandurangan Vijayanand Mitchell Kronenberg Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function Nature Communications |
| title | Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function |
| title_full | Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function |
| title_fullStr | Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function |
| title_full_unstemmed | Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function |
| title_short | Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function |
| title_sort | crohn s disease associated variant in laccase domain containing 1 lacc1 modulates t cell gene expression metabolism and t cell function |
| url | https://doi.org/10.1038/s41467-025-57744-3 |
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