美国哈佛医学院布列根和妇女医院Soumya Raychaudhuri等人在研究中取得进展。他们利用单细胞多模态数据的动态调控，揭示了与自身免疫性疾病遗传性相关的免疫细胞状态。2023年11月30日，国际学术期刊《自然—遗传学》发表了这一成果。

为了确定与细胞状态基因表达模式相关的可及性染色质非编码区域，研究人员利用多模式单核RNA和转座酶可及性染色质（ATAC）测序数据，对12名供体的发炎滑膜组织中28,674个细胞进行了分析。具体来说，研究使用多变量泊松模型来预测单核RNA测序主成分的峰值可及性。对于14种自身免疫性疾病，研究发现，与细胞状态不变（"cs-invariant"）峰相比，免疫细胞类型中依赖于细胞状态（"动态"）的染色质可及性峰具有遗传性。

这些动态峰标记了与外周辅助性T细胞、调节性T细胞、树突状细胞和STAT1⁺CXCL10⁺髓系细胞状态相关的调控元件。该研究表明动态调控元件有助于精确识别富含疾病关键基因变异的细胞状态。

据悉，在类风湿性关节炎等自身免疫性疾病中，免疫系统会攻击人自身细胞。了解非编码自身免疫风险变体致病机制的细胞状态，对于其治疗方法的研发至关重要。

附：英文原文

Title: Dynamic regulatory elements in single-cell multimodal data implicate key immune cell states enriched for autoimmune disease heritability

Author: Gupta, Anika, Weinand, Kathryn, Nathan, Aparna, Sakaue, Saori, Zhang, Martin Jinye, Donlin, Laura, Wei, Kevin, Price, Alkes L., Amariuta, Tiffany, Raychaudhuri, Soumya

Issue&Volume: 2023-11-30

Abstract: In autoimmune diseases such as rheumatoid arthritis, the immune system attacks the body’s own cells. Developing a precise understanding of the cell states where noncoding autoimmune risk variants impart causal mechanisms is critical to developing curative therapies. Here, to identify noncoding regions with accessible chromatin that associate with cell-state-defining gene expression patterns, we leveraged multimodal single-nucleus RNA and assay for transposase-accessible chromatin (ATAC) sequencing data across 28,674 cells from the inflamed synovial tissue of 12 donors. Specifically, we used a multivariate Poisson model to predict peak accessibility from single-nucleus RNA sequencing principal components. For 14 autoimmune diseases, we discovered that cell-state-dependent (‘dynamic’) chromatin accessibility peaks in immune cell types were enriched for heritability, compared with cell-state-invariant (‘cs-invariant’) peaks. These dynamic peaks marked regulatory elements associated with T peripheral helper, regulatory T, dendritic and STAT1+CXCL10+ myeloid cell states. We argue that dynamic regulatory elements can help identify precise cell states enriched for disease-critical genetic variation.

DOI: 10.1038/s41588-023-01577-7

Source: https://www.nature.com/articles/s41588-023-01577-7