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ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice

Radhika Mathur1,2, Burak H Alver3, Adrianna K San Roman1,4

  • 1Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

Nature Genetics
|December 13, 2016
PubMed

Insights

ARID1A acts as a tumor suppressor in the mouse colon, preventing colorectal cancer (CRC) by regulating gene expression at enhancers. Its loss leads to invasive ARID1A-deficient adenocarcinomas, highlighting a novel mechanism in CRC development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • SWI/SNF (BAF) chromatin-remodeling complexes are frequently mutated in human cancers (~20%).
  • ARID1A is the most commonly mutated subunit, but its role in tumorigenesis is not fully understood.
  • APC/β-catenin signaling is critical in common intestinal cancers.

Purpose of the Study:

  • To investigate the tumor-suppressive function of Arid1a in the mouse colon.
  • To understand the mechanism by which ARID1A inactivation promotes colorectal cancer (CRC).
  • To explore the role of ARID1A in regulating gene expression via chromatin remodeling.

Main Methods:

  • Utilized mouse models to study Arid1a function in the colon and small intestine.
  • Generated and characterized ARID1A-deficient adenocarcinomas.
  • Analyzed gene expression and chromatin accessibility in ARID1A-deficient tumors.
  • Investigated the targeting of SWI/SNF complexes to enhancers.

Main Results:

  • Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine.
  • ARID1A-deficient adenocarcinomas in mice closely resemble human CRC and lack APC/β-catenin pathway alterations.
  • ARID1A targets SWI/SNF complexes to enhancers, coordinating with transcription factors for gene activation.
  • ARID1B compensates for ARID1A loss, but SWI/SNF targeting and enhancer control are impaired, leading to widespread gene dysregulation.

Conclusions:

  • ARID1A inactivation promotes tumorigenesis in the colon through dysregulation of enhancer-mediated gene expression.
  • ARID1A's tumor-suppressive function is primarily linked to its role in controlling gene regulation at enhancers.
  • This study provides a new model for colon cancer and implicates enhancer regulation in ARID1A-driven tumor suppression.

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