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<p>Genome wide association studies (GWAS) identify many risks for Crohn’s disease (CD), including a site near the metabolism gene laccase domain containing 1 (<i>LACC1</i>). We previously found this site near <i>LACC1</i> was associated with decreased <i>LACC1</i> 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 <i>LACC1</i>. Direct association of disease-risk variants with lower <i>LACC1</i> pre-mRNA in human CD4<sup>+</sup> T cells is confirmed by comparing transcripts from each allele from donors heterozygous for the <i>LACC1</i> CD-risk allele. Using gene editing, we validate the function of this promoter region in <i>LACC1</i> expression in T cells. Human CD4<sup>+</sup> T cells with <i>LACC1</i> 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 <i>LACC1</i> variants to colitis by attributing promoter region variants to changes in T cell metabolism and function.</p>

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Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月15日

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  • Yingcong Li,
  • Gabriel Ascui,
  • Martina Dicker,
  • Thomas Riffelmacher,
  • Vivek Chandra,
  • Benjamin Schmiedel,
  • Ting-Fang Chou,
  • Pandurangan Vijayanand,
  • Mitchell Kronenberg

摘要

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.