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Spatial clustering and common regulatory elements lead to TGF-β induced concerted gene expression

ABSTRACT: Cellular responses require temporally concerted transcriptional regulation of multiple genes. A single-input-module motif with one transcription factor regulating multiple target genes can generate the coordinated gene expression. In eukaryotic cells, the local environment of a gene characterized by histone modifications, DNA methylations, and the three-dimensional chromosome structure also regulates its transcriptional activity. To examine how the local environment and transcriptional factor regulation is coupled, we performed combined analysis of time-course RNA-seq data of TGF-β treated MCF10A cells and corresponding epigenome and Hi-C data. We discovered, genes co-regulated by a common transcription factor has tendency to be close both in the linear DNA sequence and spatially. Specifically, we identified local spatial organization of over a hundred of AP1-regulated genes, and competition between hetero- and homo-dimeric AP1 fine-tunes the complex structure leading to differential expression of downstream genes sharing similar local environment. We suggest this spatial organization as a general regulation principle.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122093 | GEO | 2019/01/30

REPOSITORIES: GEO

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Project description:The development of the human malaria parasite Plasmodium falciparum is controlled by coordinated changes in gene expression throughout its complex life cycle, but the corresponding regulatory mechanisms are incompletely understood. To study the relation between genome architecture and gene regulation in Plasmodium, we studied the genome structure of P. falciparum at three time points during its erythrocytic (asexual) cycle. Using chromosome conformation capture coupled with next-generation sequencing technology (Hi-C), we obtained high-resolution chromosomal contact maps, which we then used to construct a consensus three-dimensional genome structure for each time point. We observe strong clustering of centromeres, telomeres, ribosomal DNA and virulence genes, resulting in a complex architecture that cannot be explained by a simple volume exclusion model. Internal virulence gene clusters appear to be an important factor in shaping the genome architecture as they exhibit domain-like structures similar to topological domains in mammalian genomes. Midway during the cell cycle, at the highly transcriptionally active trophozoite stage, the genome adopts a more open chromatin structure with increased chromosomal intermingling. In addition, we observed reduced expression of genes located in spatial proximity to the repressive subtelomeric center, and colocalization of distinct groups of parasite-specific genes with coordinated expression profiles. Overall, our results are indicative of a strong association between the P. falciparum spatial genome organization and gene expression. Understanding the molecular processes involved in genome conformation dynamics could contribute to the discovery of novel antimalarial strategies. Analysis of the spatial organization of the P. falciparum genome at three stages of the erythrocytic cycle using chromosome conformation capture coupled with next generation sequencing (Hi-C). As a control, we included one sample for which chromatin contacts were not preserved by crosslinking of DNA and proteins.

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Spatial clustering and common regulatory elements lead to TGF-β induced concerted gene expression

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