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Genome-wide profiling of Argonaute-chromosome interactions [ChIP-Seq]

ABSTRACT: Argonuate proteins are the central components of the RNA-induced silencing complex (RISC) which execute small RNA-mediated gene regulation mainly in the cytoplasm and their nuclear functions in mammalian cells remain largely unknown. Here we show that in human cancer cells Ago1 is pervasively associated with chromosomal loci throughout the genome with the association centered mostly on actively transcribed promoters. Ago1 but not Ago2 physically interacts with RNA polymerase II (RNAP II) in the nucleus. Moreover, genes bound by Ago1 are significantly enriched for several cancer related pathways. Detailed analysis of these genes including PIK3CA, PRKCH, CDC6 and RRM1 verified Ago1-mediated transcriptional gene regulation through Ago1-promoter interactions. We also found a strong correlation between Ago1-bound genes and genes downregulated by Ago1 depletion which, phenotypically, leads to inhibition of proliferation in different cancer cells. Therefore, our findings reveal the first landscape of human Ago1-chromosomal interactions which may drive oncogenic programs in cancer cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE40536 | GEO | 2013/09/27

SECONDARY ACCESSION(S): PRJNA174235

REPOSITORIES: GEO

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Project description:Higher-order chromosomal organization for transcription regulation is poorly understood in eukaryotes. Using genome-wide Chromatin Interaction Analysis with Paired-End-Tag sequencing (ChIA-PET), we mapped long-range chromatin interactions associated with RNA polymerase II in human cells and uncovered widespread promoter-centered intragenic, extragenic, and intergenic interactions. These interactions further aggregated into higher-order clusters, wherein proximal and distal genes were engaged through promoter-promoter interactions. Most genes with promoter-promoter interactions were active and transcribed cooperatively, and some interacting promoters could influence each other implying combinatorial complexity of transcriptional controls. Comparative analyses of different cell lines showed that cell-specific chromatin interactions could provide structural frameworks for cell-specific transcription, and suggested significant enrichment of enhancer-promoter interactions for cell-specific functions. Furthermore, genetically-identified disease-associated noncoding elements were found to be spatially engaged with corresponding genes through long-range interactions. Overall, our study provides insights into transcription regulation by three-dimensional chromatin interactions for both housekeeping and cell-specific genes in human cells. RNA polymerase II (RNAPII) bound chromatin interactions were extracted with Chromatin Interaction Analysis with Paired-End Tag (ChIA-PET) sequencing, in order to study the transcription regulations with RNAPII-associated long-range chromatin interactions. Five cell lines, namely MCF7 (ATCC# HTB-22), K562 (ATCC# CCL-243), HCT116 (ATCC# CCL-247), HeLa (ATCC# CCL-2.2), and NB4 (Roussel and Lanotte, 2001) (provided by Dr. Sherman Weissman, Yale University), were grown under standard culture conditions and harvested at log phase. Harvested cells were cross-linked using 1% formaldehyde followed by neutralization with 0.2M glycine. Chromatin was isolated and subjected to ChIA-PET protocol as described in Fullwood et al (Fullwood et al: An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 2009, 462(7269):58-64). The ChIA-PET sequence reads were processed and analyzed using ChIA-PET Tool (Li et al: ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing. Genome Biol 2010, 11(2):R22).

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Genome-wide profiling of Argonaute-chromosome interactions [ChIP-Seq]

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