Capturing 3D Chromatin Maps of Human Primary Monocytes: Insights From High-Resolution Hi-C.

Yu Xia,Xin Liu,Shuai Zong,Xiaowen Liu,Bin Cui,Yulian Jiao,Laicheng Wang,Chunyan Ma,Shengnan Hu,Tao Liu,Huanxin Sun,Yueran Zhao,Wenli Mu,Ying Gao

doi:10.3389/fimmu.2022.837336

Abstract

Although the variation in chromatin architecture during adaptive immune responses has been thoroughly investigated, the 3D landscape of innate immunity is still unknown. Herein, chromatin regulation and heterogeneity among human primary monocytes were investigated. Peripheral blood was collected from two healthy persons and two patients with systemic lupus erythematosus (SLE), and CD14+ monocytes were selected to perform Hi-C, RNA-seq, ATAC-seq and ChIP-seq analyses. Raw data from the THP1 cell line Hi-C library were used for comparison. For each sample, we constructed three Hi-C libraries and obtained approximately 3 billion paired-end reads in total. Resolution analysis showed that more than 80% of bins presented depths greater than 1000 at a 5 kb resolution. The constructed high-resolution chromatin interaction maps presented similar landscapes in the four individuals, which showed significant divergence from the THP1 cell line chromatin structure. The variability in chromatin interactions around HLA-D genes in the HLA complex region was notable within individuals. We further found that the CD16-encoding gene (FCGR3A) is located at a variable topologically associating domain (TAD) boundary and that chromatin loop dynamics might modulate CD16 expression. Our results indicate both the stability and variability of high-resolution chromatin interaction maps among human primary monocytes. This work sheds light on the potential mechanisms by which the complex interplay of epigenetics and spatial 3D architecture regulates chromatin in innate immunity.

Highlights

Chromatin is hierarchically packaged into the nucleus of higher eukaryotes to organize the threedimensional (3D) genome structure [1], which is responsible for precise transcriptional regulation by facilitating or restricting regulatory element interactions [2]
Due to the THP1 cell line was established from leukaemia patient, we especially checked the status of chromosomal rearrangement
We found that the primary monocyte samples showed roughly similar chromatin landscapes in terms of chromatin interaction frequencies, interaction matrices, A/B compartments and topologically associating domain (TAD) boundaries, and few consistent patterns were found between the systemic lupus erythematosus (SLE) patients and healthy controls

Summary

Introduction

Chromatin is hierarchically packaged into the nucleus of higher eukaryotes to organize the threedimensional (3D) genome structure [1], which is responsible for precise transcriptional regulation by facilitating or restricting regulatory element interactions [2]. The 3D genome architecture associated with cell fate and function under both physiological and pathological. Chromatin interactions play a fundamental role in establishing and maintaining the functions of immune cells during development, differentiation and activation in autoimmune diseases [12, 13]. Recent research combining associated genetic variants identified from Genome-wide Association Studies (GWASs) with 3D structures observed in different immune cell physiological states has revealed potential regulatory connections of these noncoding region variants related to the pathogenesis of autoimmune diseases [20, 21]; this work has yielded pivotal insights into how autoimmunity is triggered by susceptible polymorphisms [22]

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Conclusion