Novel insights into chromosomal conformations in cancer

Abstract

Exploring gene function is critical for understanding the complexity of life. DNA sequences and the three-dimensional organization of chromatin (chromosomal interactions) are considered enigmatic factors underlying gene function, and interactions between two distant fragments can regulate transactivation activity via mediator proteins. Thus, a series of chromosome conformation capture techniques have been developed, including chromosome conformation capture (3C), circular chromosome conformation capture (4C), chromosome conformation capture carbon copy (5C), and high-resolution chromosome conformation capture (Hi-C). The application of these techniques has expanded to various fields, but cancer remains one of the major topics. Interactions mediated by proteins or long noncoding RNAs (lncRNAs) are typically found using 4C-sequencing and chromatin interaction analysis by paired-end tag sequencing (ChIA-PET). Currently, Hi-C is used to identify chromatin loops between cancer risk-associated single-nucleotide polymorphisms (SNPs) found by genome-wide association studies (GWAS) and their target genes. Chromosomal conformations are responsible for altered gene regulation through several typical mechanisms and contribute to the biological behavior and malignancy of different tumors, particularly prostate cancer, breast cancer and hematologic neoplasms. Moreover, different subtypes may exhibit different 3D-chromosomal conformations. Thus, C-tech can be used to help diagnose cancer subtypes and alleviate cancer progression by destroying specific chromosomal conformations. Here, we review the fundamentals and improvements in chromosome conformation capture techniques and their clinical applications in cancer to provide insight for future research.

Keywords: Cancer; Chromosomal conformations; Chromosome conformation capture; Diagnosis; Treatment.

Fig. 1

Overview of 3C-based C-techniques. After crosslinking, chromatin is digested into 4-10 kb pieces by restriction enzymes, followed by ligation and reverse crosslinking to change the crosses into lines. An additional digestion step is added in 4C. LMA is used instead of PCR, which is commonly used in 5C; biotinylation and streptavidin are used in Hi-C, and a chromatin immunoprecipitation (CHIP) step is added in ChIA-PET

Fig. 2

Several mechanisms for forming chromosomal loops in cancer. Pol II (orange), transcription factors (green) and co-transcription factors (yellow) are always recruited by long-range loop mediators in transcription factories. a Most loops are mediated by CTCF and cohesin, with or without other mediators. b ERα is another common mediator that functions after binding E2 and entering the nucleus. c Pol II can mediate long-range loops between promoters, suggesting that promoters sometimes act as enhancers. d MED1 acts as a chromosomal loop mediator only when it is phosphorylated. e Some lncRNAs can mediate chromosomal loops. f CUX1 is special in that it mediates the binding of two enhancers to one promoter, and when its expression is reduced to 50%, it mediates the binding of one enhancer to one promoter