Advancing Physiology with Expanded Multi-Omics.
Advancing Physiology with Expanded Multi-Omics.
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DOI：
10.1093/function/zqac031
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发表时间：
2022
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世纪后半叶，分子生物学的进步使人类生物学的观点从完全基于器官系统转变为强调分子。在过去的十年左右，人类生物学的观点已经开始再次转变，这一次越来越多地认识到人类是分子系统，其中分子相互作用，在细胞和器官系统的背景下呈现出涌现的特性。越来越多的人认识到人类是分子系统，导致了分子系统医学这一新的科学学科的出现。分子系统医学的支柱之一是将基因组规模的分子分析或组学与生理学相结合。利用组学来推进生理学的想法并不新鲜。新的是，在过去10-15年中，组学工具箱和知识库的大幅扩展为这一领域提供了前所未有的机会。第一篇RNA测序论文发表于15年前。从那时起，已经开发了基于深度测序的方法，用于染色质构象（例如Hi-C和Micro-C），染色质可及性（例如，测序的转座酶可及染色质测定，或ATAC-seq），组蛋白结合（例如，靶下切割和标签化，或CUT&Tag）和DNA甲基化（例如，还原亚硫酸氢盐测序，或RRBS）的基因组规模分析。用于RNA（包括RNA修饰，例如甲基化RNA免疫沉淀测序或MeRIP-seq）、小的非编码RNA、蛋白质和代谢物的基因组规模分析的方法也在继续发展。许多这些测定现在可以在单细胞或单核中进行（即单细胞组学），如最近关于人类泛组织单细胞转录组图谱的报道所示。此外，一些组学分析可以与天然组织中细胞的空间分布相结合（即空间组学）。多组学的力量通过生物信息学的进步和与计算建模的整合而得以实现和放大。例如，最近的一项研究使用实验分析和数学建模来量化长距离染色质相互作用对单细胞转录活性的影响3。分析揭示了增强子的转录效应和增强子与启动子的接触概率之间的非线性关系，这可能是由于增强子-启动子相互作用的瞬时性质加上单个细胞中较慢的启动子爆发动力学。
Advances in molecular biology in the second half of the 20th century shifted the view of human biology from one that was exclusively based on organ systems to one that emphasized molecules. In the last decade or so, the view of human biology has begun to shift again, this time towards an increasing recognition that humans are molecular systems in which molecules interact to take on emergent properties within the context of cells and organ systems. The increasing recognition that humans are molecular systems has led to the emergence of the new scientific discipline of molecular systems medicine 1. One of the pillars of molecular systems medicine is the integration of genome-scale molecular analysis, or omics, with physiology. The idea of using omics to advance physiology is not new. What is new is the unprecedented opportunity in this area provided by the substantial expansion of omics toolbox and knowledgebase in the last 10–15 years. The first RNA-seq paper was published 15 years ago. Since then, deep sequencing-based methods have been developed for genome-scale analysis of chromatin conformation (eg, Hi-C and Micro-C), chromatin accessibility (eg, assay for transposase-accessible chromatin with sequencing, or ATAC-seq), histone binding (eg, cleavage under targets and tagmentation, or CUT&Tag), and DNA methylation (eg, reduced representation bisulfite sequencing, or RRBS). Methods for genome-scale analysis of RNA (including RNA modifications, eg, methylated RNA immunoprecipitation sequencing, or MeRIP-seq), small noncoding RNA, proteins, and metabolites have also continued to advance. Many of these assays can now be performed in single cells or single nuclei (ie, single cell omics) as illustrated by recent reports of pan-tissue single-cell transcriptome atlases in humans 2. Furthermore, several omic assays may be integrated with spatial distribution of cells in native tissues (ie, spatial omics).The power of multi-omics is enabled and amplified by advances in bioinformatics and the integration with computational modeling. For example, a recent study used experimental analysis and mathematical modelling to quantify the effect of long-range chromatin interactions on transcriptional activities in single cells 3. The analysis revealed a nonlinear relation between the transcriptional effect of an enhancer and the enhancer’s contact probabilities with the promoter, which might arise from the transient nature of enhancer-promoter interactions coupled with slower promoter bursting dynamics in individual cells.