3D Genome Rewiring Alters Gene Expression in 15 primary human cancer types

Amazing stuff! Cancer is history (soon)! This seems to be an impressive work!

"... leveraging The Cancer Genome Atlas (TCGA) and high-throughput conformational and sequencing techniques to map the 3D cancer genome. The findings ... highlight how changes to enhancer binding influence gene expression in tumors. ...

developed HiChIP, which captures 3D structural information about the genome at specific loci and with smaller numbers of cells. It works by first crosslinking DNA-associated proteins, immunoprecipitating the crosslinked proteins, and then sequencing the bound DNA. ...

To find enhancer activity in cancer genomes, the team applied HiChip. Using histone H3 lysine 27 acetylation (H3K27ac) as a target for enhancer sequences, the researchers profiled 69 tumors from 15 different types of cancer available in TCGA to determine how enhancer binding activity changed across cancers. These samples included information from ATAC-seq, RNA-seq, and whole genome sequencing, allowing the team to combine their conformation data with that of accessible chromatin regions, gene expression, and mutations.

The researchers observed DNA loops with unique interactions of enhancer elements not previously reported. Some of these connections, for example those at the locus for the oncogene MYC, differed between cancer types; in one colon tumor, the researchers observed H34K27ac enrichment at the 5’ end of this gene, whereas in a liver tumor, they saw these marks in a 3’ regulatory region.

As they explored enhancer rewiring across 110 oncogenes, the team noticed three overall patterns:

the same enhancer rewiring occurred around a gene across cancer types,

a specific enhancer rewiring pattern only occurred in one cancer type, and

as in the example of MYC—enhancer rewiring patterns differed at the same gene in different cancers.

Next, the researchers investigated how enhancer rewiring and other DNA structural changes, such as gene duplications that result in higher gene expression, affected oncogene expression in their samples. Leveraging their HiChIP data with information from RNA-seq and whole genome sequencing, the researchers found that increased enhancer activity led to increased mRNA expression in more than 70 percent of oncogenes studied. ..."

From the abstract:

"Genome conformation underlies transcriptional regulation by distal enhancers, and genomic rearrangements in cancer can alter critical regulatory interactions.

Here we profiled the three-dimensional genome architecture and enhancer connectome of 69 tumor samples spanning 15 primary human cancer types from The Cancer Genome Atlas.

We discovered the following three archetypes of enhancer usage for over 100 oncogenes across human cancers: static, selective gain or dynamic rewiring. Integrative analyses revealed the enhancer landscape of noncancer cells in the tumor microenvironment for genes related to immune escape.

Deep whole-genome sequencing and enhancer connectome mapping provided accurate detection and validation of diverse structural variants across cancer genomes and revealed distinct enhancer rewiring consequences from noncoding point mutations, genomic inversions, translocations and focal amplifications. Extrachromosomal DNA promoted more extensive enhancer rewiring among several types of focal amplification mechanisms.

These results suggest a systematic approach to understanding genome topology in cancer etiology and therapy."

3D Genome Rewiring Alters Gene Expression in Cancer | The Scientist "Investigating how mutations in tumors alter DNA’s 3D structure—and subsequently, regulatory sequences called enhancers—can offer new treatment opportunities."

Three-dimensional genome landscape of primary human cancers (open access)

Fig. 1: HiChIP identifies high-resolution chromosome conformation in primary human cancers across multiple scales.

Fig. 4: Integration of WGS and HiChIP identifies cancer-relevant regulatory mutations and target genes.