小柯机器人

美国斯坦福大学William J. Greenleaf研究组发现，人类头皮的单细胞染色质和转录组综合分析鉴定出毛发和皮肤疾病的基因调控程序和关键细胞类型。相关论文于2023年7月27日在线发表在《自然—遗传学》杂志上。

研究人员从健康对照组和斑秃患者的头皮组织中生成了匹配的单细胞染色质图谱和转录组，从而确定了毛囊微环境的不同细胞类型。通过对这些数据集进行多层次的细胞分辨率分析，研究人员推断出的增强子-基因联系比以前的方法多50-100%，并表明高度调控基因的聚集增强子可及性可预测基因的表达。

研究人员利用这些基因调控图谱优先考虑与雄激素性脱发（AGA）、湿疹和其他复杂性状的病理生物学有关的细胞类型、基因和因果变异。AGA全基因组关联研究信号在真皮乳头调控区域中富集，并支持了这些细胞在AGA发病机制中的驱动作用。最后，研究人员训练了机器学习模型来提出通过破坏转录因子结合影响基因表达的单核苷酸多态性，从而预测了AGA和湿疹的候选功能性单核苷酸多态性。

据介绍，全基因组关联研究发现了许多与毛发和皮肤疾病相关的基因位点，但要确定致病变体，需要破译相关细胞类型中的基因调控网络。

附：英文原文

Title: Integrated single-cell chromatin and transcriptomic analyses of human scalp identify gene-regulatory programs and critical cell types for hair and skin diseases

Author: Ober-Reynolds, Benjamin, Wang, Chen, Ko, Justin M., Rios, Eon J., Aasi, Sumaira Z., Davis, Mark M., Oro, Anthony E., Greenleaf, William J.

Issue&Volume: 2023-07-27

Abstract: Genome-wide association studies have identified many loci associated with hair and skin disease, but identification of causal variants requires deciphering of gene-regulatory networks in relevant cell types. We generated matched single-cell chromatin profiles and transcriptomes from scalp tissue from healthy controls and patients with alopecia areata, identifying diverse cell types of the hair follicle niche. By interrogating these datasets at multiple levels of cellular resolution, we infer 50–100% more enhancer–gene links than previous approaches and show that aggregate enhancer accessibility for highly regulated genes predicts expression. We use these gene-regulatory maps to prioritize cell types, genes and causal variants implicated in the pathobiology of androgenetic alopecia (AGA), eczema and other complex traits. AGA genome-wide association studies signals are enriched in dermal papilla regulatory regions, supporting the role of these cells as drivers of AGA pathogenesis. Finally, we train machine learning models to nominate single-nucleotide polymorphisms that affect gene expression through disruption of transcription factor binding, predicting candidate functional single-nucleotide polymorphism for AGA and eczema.

DOI: 10.1038/s41588-023-01445-4

Source: https://www.nature.com/articles/s41588-023-01445-4

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex