TY - JOUR
T1 - Global loss of promoter–enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis
AU - Zhu, Yizhou
AU - Lee, Hayan
AU - White, Shannon
AU - Weimer, Annika K.
AU - Monte, Emma
AU - Horning, Aaron
AU - Nevins, Stephanie A.
AU - Esplin, Edward D.
AU - Paul, Kristina
AU - Krieger, Gat
AU - Shipony, Zohar
AU - Chiu, Roxanne
AU - Laquindanum, Rozelle
AU - Karathanos, Thomas V.
AU - Chua, Melissa W.Y.
AU - Mills, Meredith
AU - Ladabaum, Uri
AU - Longacre, Teri
AU - Shen, Jeanne
AU - Jaimovich, Ariel
AU - Lipson, Doron
AU - Kundaje, Anshul
AU - Greenleaf, William J.
AU - Curtis, Christina
AU - Ford, James M.
AU - Snyder, Michael P.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/10
Y1 - 2024/10
N2 - Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter–enhancer (P–E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P–E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression.
AB - Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter–enhancer (P–E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P–E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression.
KW - Adenomatous Polyposis Coli/genetics
KW - Carcinogenesis/genetics
KW - Cell Transformation, Neoplastic/genetics
KW - Chromatin/metabolism
KW - Colorectal Neoplasms/genetics
KW - Enhancer Elements, Genetic
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Promoter Regions, Genetic
UR - http://www.scopus.com/inward/record.url?scp=85207877204&partnerID=8YFLogxK
U2 - 10.1038/s43018-024-00823-z
DO - 10.1038/s43018-024-00823-z
M3 - Article
C2 - 39478119
AN - SCOPUS:85207877204
SN - 2662-1347
VL - 5
SP - 1697
EP - 1712
JO - Nature Cancer
JF - Nature Cancer
IS - 11
ER -
