Morphine Re-Arranges Chromatin Spatial Architecture of Primate Cortical Neurons

Abstract

The expression of linear DNA sequence is precisely regulated by the three-dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neurons is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons. After receiving continuous morphine administration for 90 days on rhesus monkeys, we discovered that morphine re-arranged chromosome territories, with a total of 391 segmented compartments being switched. Morphine altered over half of the detected topologically associated domains (TADs), most of which exhibited a variety of shifts, followed by separating and fusing types. Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops. Moreover, all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops, and were further validated for changed expression. Collectively, an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects. Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.

SEQSIM – A novel bioinformatics tool for comparisons of upstream gene regions – a case study of calcium binding protein spermatid associated 1 (CABS1)

“…Recent studies have begun to shed light on the intricate relationship between 3D chromatin architecture and gene expression under various conditions. For instance, research on primate cortical neurons exposed to morphine showed rearrangement in chromosome territories and alterations in TADs, which were associated with changes in gene expression(48). In the pursuit of deciphering 3D chromatin architecture, methodologies such as chromosome conformation capture (3C) and its derivative Hi-C, as well as techniques like DNA-FISH, have been instrumental.…”