Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Apr 4;84(7):1365-1376.e7.
doi: 10.1016/j.molcel.2024.02.007. Epub 2024 Mar 6.

Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation

Kyung Lock Kim  1 , Gilbert J Rahme  1 , Viraat Y Goel  2 , Chadi A El Farran  1 , Anders S Hansen  2 , Bradley E Bernstein  3
Affiliations

Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation

Kyung Lock Kim et al. Mol Cell. .

Abstract

Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth factor (FGF) oncogenes but is disrupted by DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The boundary contains an array of CTCF sites that enforce adjacent TADs, one containing FGF genes and the other containing ANO1 and its putative enhancers, which are specifically active in GIST and its likely cell of origin. We show that coordinate disruption of four CTCF motifs in the boundary fuses the adjacent TADs, allows the ANO1 enhancer to contact FGF3, and causes its robust induction. High-resolution micro-C maps reveal specific contact between transcription initiation sites in the ANO1 enhancer and FGF3 promoter that quantitatively scales with FGF3 induction such that modest changes in contact frequency result in strong changes in expression, consistent with a causal relationship.

Keywords: ANO1; CTCF insulator; DNA methylation; FGF3; FGF4; SDH deficiency; chromatin; enhancer regulation; gastrointestinal stromal tumor; genome topology.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests B.E.B. declares outside interests in Fulcrum Therapeutics, HiFiBio, Arsenal Biosciences, Chroma Medicine, Cell Signaling Technologies, and Design Pharmaceuticals. V.Y.G. and A.S.H. have filed a provisional patent on RCMC.

Similar articles

See all similar articles

Cited by

References

    1. Furlong EEM, and Levine M (2018). Developmental enhancers and chromosome topology. Science 361, 1341–1345. 10.1126/science.aau0320. - DOI - PMC - PubMed
    1. Cramer P. (2019). Organization and regulation of gene transcription. Nature 573, 45–54. 10.1038/s41586-019-1517-4. - DOI - PubMed
    1. Heinz S, Romanoski CE, Benner C, and Glass CK (2015). The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol 16, 144–154. 10.1038/nrm3949. - DOI - PMC - PubMed
    1. Rozowsky J, Gao J, Borsari B, Yang YT, Galeev T, Gürsoy G, Epstein CB, Xiong K, Xu J, Li T, et al. (2023). The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models. Cell 186, 1493–1511.e40. 10.1016/j.cell.2023.02.018. - DOI - PMC - PubMed
    1. Schoenfelder S, and Fraser P (2019). Long-range enhancer-promoter contacts in gene expression control. Nat. Rev. Genet 20, 437–455. 10.1038/s41576-019-0128-0. - DOI - PubMed

LinkOut - more resources