Abstract
Chromatin conformation plays a key role in regulating gene expression and controlling cell differentiation. However, the whole-genome chromatin conformation changes that occur during leukemia cell differentiation are poorly understood. Here, we characterized the changes in chromatin conformation, histone states, chromatin accessibility, and gene expression using an all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation model. The results showed that the boundaries of topological associated domains (TADs) were stable during differentiation; however, the chromatin conformations within several specific TADs were obviously changed. By combining H3K4me3, H3K27ac, and Hi-C signals, we annotated the differential gene-regulatory chromatin interactions upon ATRA induction. The gains and losses of the gene-regulatory chromatin interactions are significantly correlated with gene expression and chromatin accessibility. Finally, we found that the loss of GATA2 expression and DNA binding are crucial for the differentiation process, and changes in the chromatin structure around the GATA2 regulate its expression upon ATRA induction. This study provided both statistical insights and experimental details regarding the relationship between chromatin conformation changes and transcription regulation during leukemia cell differentiation, and the results suggested that the chromatin conformation is a new type of potential drug target for cancer therapy.
Highlights
Hierarchical conformations formed by chromosomes play a pivotal role in the regulation of gene expression
Compartment and topological associated domains (TADs) position did not significantly change upon all-trans retinoic acid (ATRA) induction To determine whether the whole-genome chromatin conformation changes during ATRA-induced differentiation, we generated high-throughput chromosome conformation capture (Hi-C) libraries from 2 independent biological replicates of control and ATRA-treated HL-60 cells (Fig. S1) using a modified in situ Hi-C protocol (Methods)
While the prominent lobulation of the cell nucleus could be observed in the ATRA-treated cells under a fluorescence microscope (Fig. S3)[27], the contact frequency between each chromosome appeared unchanged in the Hi-C data (Fig. 1a)
Summary
Hierarchical conformations formed by chromosomes play a pivotal role in the regulation of gene expression. Chromatin conformation has been shown to play an important role in transcription regulation and drug response[18,19]. The dynamic chromatin conformation signatures in the HOXA locus have been shown to correlate with gene expression dynamics and are used to classify the leukemia types[20,21]. Studies have demonstrated that the major regulator of leukemia cell differentiation, i.e., c-Myb, could be modulated by upstream regulatory regions through chromatin interaction[22]. The whole-genome chromatin conformation change during leukemia cell differentiation and its relationship with transcription regulation have not been well characterized
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