한빛사논문
- 조회512
Dana-Farber Cancer Institute Broad Institute of MIT, Harvard and Harvard University
Kyung Lock Kim,1,2,3 Gilbert J. Rahme,1,2,3 Viraat Y. Goel,2,4,5 Chadi A. El Farran,1,2,3 Anders S. Hansen,2,4,5 and Bradley E. Bernstein 1,2,3,6,*
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA02215, USA
2Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA02142,USA
3Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA02215, USA
4Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA02139, USA
5Koch Institute for Integrative Cancer Research, Cambridge, MA02139, USA
6Lead contact
*Corresponding author: correspondence to Bradley E. Bernstein
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.
논문정보
- Research article
- 2024년 03월 (BRIC 등록일 2024-04-02)
- 국외 연구진
- 생명과학 > 노화/암생물학
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