小柯机器人

美国维吉尼亚大学Clint L. Miller、Chongzhi Zang等研究人员，合作利用单核染色质可及性分析揭示冠状动脉疾病风险的调控机制。该项研究成果于2022年5月19日在线发表在《自然—遗传学》杂志上。

研究人员应用转座酶可接触染色质的单核检测与测序，对41名不同阶段的冠状动脉疾病（CAD）患者的28,316个冠状动脉节段的核进行分析，发现了14个不同的细胞群。研究人员在所有细胞中绘制了约32万个可访问的位点，确定了细胞类型的特异性元件和转录因子，并对功能性CAD风险变体进行了优先排序。研究人员确定了平滑肌细胞过渡状态的元件（例如，纤维肌细胞）和预测会改变平滑肌细胞和巨噬细胞对MRAS（3q22）和LIPA（10q23）特异性调节的功能变体。研究人员进一步挑选了关键的驱动转录因子，如PRDM16和TBX2。总之，这个单核图谱为解释整个CAD风险连续体的调控机制提供了关键的一步。

据介绍，CAD是一种复杂的炎症性疾病，涉及跨细胞类型的遗传影响。全基因组关联研究已经确定了200多个与CAD相关的位点，其中大部分风险变体位于影响顺式调控元件的非编码DNA序列中。

附：英文原文

Title: Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk

Author: Turner, Adam W., Hu, Shengen Shawn, Mosquera, Jose Verdezoto, Ma, Wei Feng, Hodonsky, Chani J., Wong, Doris, Auguste, Galle, Song, Yipei, Sol-Church, Katia, Farber, Emily, Kundu, Soumya, Kundaje, Anshul, Lopez, Nicolas G., Ma, Lijiang, Ghosh, Saikat Kumar B., Onengut-Gumuscu, Suna, Ashley, Euan A., Quertermous, Thomas, Finn, Aloke V., Leeper, Nicholas J., Kovacic, Jason C., Bjrkgren, Johan L. M., Zang, Chongzhi, Miller, Clint L.

Issue&Volume: 2022-05-19

Abstract: Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell-type-specific elements and transcription factors, and prioritized functional CAD risk variants. We identified elements in smooth muscle cell transition states (for example, fibromyocytes) and functional variants predicted to alter smooth muscle cell- and macrophage-specific regulation of MRAS (3q22) and LIPA (10q23), respectively. We further nominated key driver transcription factors such as PRDM16 and TBX2. Together, this single-nucleus atlas provides a critical step towards interpreting regulatory mechanisms across the continuum of CAD risk. Single-nucleus ATAC-seq characterization of chromatin accessibility in human coronary artery disease samples identifies cell-type- and state-specific regulatory mechanisms underlying disease risk, highlighting the roles of TBX2 and PRDM16.

DOI: 10.1038/s41588-022-01069-0

Source: https://www.nature.com/articles/s41588-022-01069-0

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