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人皮下脂肪干细胞启动子染色质修饰和 HiChIP 调控相互作用图谱

An Atlas of Promoter Chromatin Modifications and HiChIP Regulatory Interactions in Human Subcutaneous Adipose-Derived Stem Cells.

机构信息

Division of Diabetes Endocrinology and Metabolism, Departments of Medicine, Biological Chemistry and Pediatrics, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL 33701, USA.

Translational Research Institute, AdventHealth, Orlando, FL 32804, USA.

出版信息

Int J Mol Sci. 2023 Dec 28;25(1):437. doi: 10.3390/ijms25010437.

Abstract

The genome of human adipose-derived stem cells (ADSCs) from abdominal and gluteofemoral adipose tissue depots are maintained in depot-specific stable epigenetic conformations that influence cell-autonomous gene expression patterns and drive unique depot-specific functions. The traditional approach to explore tissue-specific transcriptional regulation has been to correlate differential gene expression to the nearest-neighbor linear-distance regulatory region defined by associated chromatin features including open chromatin status, histone modifications, and DNA methylation. This has provided important information; nonetheless, the approach is limited because of the known organization of eukaryotic chromatin into a topologically constrained three-dimensional network. This network positions distal regulatory elements in spatial proximity with gene promoters which are not predictable based on linear genomic distance. In this work, we capture long-range chromatin interactions using HiChIP to identify remote genomic regions that influence the differential regulation of depot-specific genes in ADSCs isolated from different adipose depots. By integrating these data with RNA-seq results and histone modifications identified by ChIP-seq, we uncovered distal regulatory elements that influence depot-specific gene expression in ADSCs. Interestingly, a subset of the HiChIP-defined chromatin loops also provide previously unknown connections between waist-to-hip ratio GWAS variants with genes that are known to significantly influence ADSC differentiation and adipocyte function.

摘要

人类脂肪来源干细胞(ADSCs)的基因组来自腹部和臀股脂肪组织库,这些组织库中存在特定于组织库的稳定表观遗传构象,这些构象影响细胞自主基因表达模式,并驱动独特的特定于组织库的功能。传统上,探索组织特异性转录调控的方法是将差异基因表达与相关染色质特征(包括开放染色质状态、组蛋白修饰和 DNA 甲基化)定义的最近邻线性距离调控区域相关联,以确定差异基因表达。这提供了重要的信息;尽管如此,由于真核染色质组织成拓扑约束的三维网络,这种方法受到限制。该网络将远程调控元件定位在与基因启动子的空间接近位置,而这些位置不能根据线性基因组距离预测。在这项工作中,我们使用 HiChIP 捕获长程染色质相互作用,以鉴定影响不同脂肪组织库中分离的 ADSC 中特定于组织库的基因差异调控的远程基因组区域。通过将这些数据与 RNA-seq 结果和 ChIP-seq 鉴定的组蛋白修饰相结合,我们发现了影响 ADSC 中特定于组织库的基因表达的远程调控元件。有趣的是,HiChIP 定义的染色质环的一部分还提供了以前未知的连接,将腰围-臀围比 GWAS 变体与已知显著影响 ADSC 分化和脂肪细胞功能的基因联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34f7/10778978/1a3b13a6ad8e/ijms-25-00437-g001.jpg

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