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DisP-seq reveals the genome-wide functional organization of DNA-associated disordered proteins.

ABSTRACT: Intrinsically disordered regions (IDRs) in DNA-associated proteins are known to influence gene regulation, but their distribution and cooperative functions in genome-wide regulatory programs remain poorly understood. Here we describe DisP-seq (disordered protein precipitation followed by DNA sequencing), an antibody-independent chemical precipitation assay that can simultaneously map endogenous DNA-associated disordered proteins genome-wide through a combination of biotinylated isoxazole precipitation and next-generation sequencing. DisP-seq profiles are composed of thousands of peaks that are associated with diverse chromatin states, are enriched for disordered transcription factors (TFs) and are often arranged in large lineage-specific clusters with high local concentrations of disordered proteins and different combinations of histone modifications linked to regulatory potential. We use DisP-seq to analyze cancer cells and reveal how disordered protein-associated islands enable IDR-dependent mechanisms that control the binding and function of disordered TFs, including oncogene-dependent sequestration of TFs through long-range interactions and the reactivation of differentiation pathways upon loss of oncogenic stimuli in Ewing sarcoma.

SUBMITTER: Xing YH

PROVIDER: S-EPMC10791585 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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DisP-seq reveals the genome-wide functional organization of DNA-associated disordered proteins.

Xing Yu-Hang YH Dong Rui R Lee Lukuo L Rengarajan Shruthi S Riggi Nicolò N Boulay Gaylor G Rivera Miguel N MN

Nature biotechnology 20230410 1

Intrinsically disordered regions (IDRs) in DNA-associated proteins are known to influence gene regulation, but their distribution and cooperative functions in genome-wide regulatory programs remain poorly understood. Here we describe DisP-seq (disordered protein precipitation followed by DNA sequencing), an antibody-independent chemical precipitation assay that can simultaneously map endogenous DNA-associated disordered proteins genome-wide through a combination of biotinylated isoxazole precipi ...[more]

PMID: 37037903

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Project description:BackgroundExtrachromosomal circular DNAs (eccDNAs) are commonly found in various tumors and play a critical role in promoting oncogenesis. However, little is known about the characteristics and nature of eccDNAs in human heart failure. The aim of this study was to comprehensively analyze eccDNAs in human heart failure caused by dilated cardiomyopathy (DCM) and explore their potential functions.MethodsCircle-Seq and RNA-Seq were performed in cardiac tissue samples obtained from patients with DCM and healthy controls to identify eccDNAs and corresponding genes. Inward PCR, outward PCR and Sanger sequencing were conducted to validate the circular structure of eccDNAs. Bioinformatics was employed to probe the transcriptional activity of eccDNAs and their potential roles in the development of DCM. Ligase assisted minicircle accumulation strategy was used to synthesize a 500 bp circular DNA with a random sequence.ResultsEccDNAs originated from all chromosomes, with the majority being less than 1 kb in size and about half containing genes or gene fragments. They were derived from specific repeat elements and primarily mapped to 5'UTR, 3'UTR, and CpG islands. Gene-rich chromosomes 17 and 19 exhibited higher eccDNA enrichment. Sequence motifs flanking eccDNA junction sites displayed frequent nucleotide repeats. The circular structure of eccDNAs were confirmed. Integration of Circle-Seq and RNA-Seq data identified that large eccDNAs can be directly transcribed in non-dividing cardiomyocytes, indicating their potential roles in gene expression. Small circular DNA elicited a stronger cytokine response than linear DNA with the same sequence.ConclusionsOur work provided a detailed profiling of eccDNAs in both healthy and DCM hearts and demonstrated the potential functions of both large and small eccDNAs. These findings enhance the comprehension of the role of eccDNAs in cardiac pathophysiology and establish a theoretical foundation for future investigations on eccDNAs in DCM.

Dataset Information

DisP-seq reveals the genome-wide functional organization of DNA-associated disordered proteins.

Publications

DisP-seq reveals the genome-wide functional organization of DNA-associated disordered proteins.

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