Monocyte-to-macrophage trans-differentiation has long been studied to better understand this immunological response and aspects of developmental processes more generally. A key question is the nature of the corresponding changes in chromatin conformation and its relationship to the transcriptome during this process. This question is especially intriguing since this trans-differentiation is not associated with progression through mitosis, often considered a necessary step for gross changes in chromosomal structure. Here, we characterized the transcriptional and genomic structural changes during macrophage development of primary human monocytes using RNA-seq and in situ Hi-C. We found that, during this transition, the genome architecture undergoes a massive remodeling to a degree not observed before between structured genomes, with changes in ~90% of the topologically associating domains (TADs). These changes in the TADs are associated with changed expression of immunological genes. These structural changes, however, differ extensively from those described recently in a study of the leukemia cell line, THP-1. Furthermore, up-regulation of the AP-1 family of genes that effected functionally important changes in the genomic structure during the differentiation of the THP-1 cells was not corroborated with the primary cells. Taken together, our results provide a comprehensive characterization of the changes in genomic structure during the monocyte-to-macrophage transition, establish a framework for the elucidation of processes underlying differentiation without proliferation, and demonstrate the importance of verifying with primary cells the mechanisms discovered with cultured cells.

中文翻译：

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原代单核细胞分化为巨噬细胞期间基因组的大规模重组。

长期以来，人们一直在研究单核细胞向巨噬细胞的转分化，以更全面地了解这种免疫反应和发育过程的各个方面。一个关键问题是染色质构象相应变化的性质及其在此过程中与转录组的关系。这个问题特别有趣，因为这种转分化与有丝分裂的进展无关，而有丝分裂通常被认为是染色体结构发生重大变化的必要步骤。在这里，我们表征了使用RNA-seq和原位原代人单核细胞巨噬细胞发育过程中的转录和基因组结构变化嗝。我们发现，在此过渡过程中，基因组架构经历了大规模的重塑，达到了结构化基因组之间前所未有的程度，其中约90％的拓扑关联域（TAD）发生了变化。TAD中的这些变化与免疫基因表达的变化有关。但是，这些结构变化与最近在白血病细胞系THP-1的研究中描述的结构变化大不相同。此外，原代细胞不能证实在THP-1细胞分化过程中影响基因组结构功能上重要变化的AP-1基因家族的上调。综上所述，我们的结果提供了单核细胞向巨噬细胞过渡过程中基因组结构变化的全面表征，