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A mutant ASXL1-BAP1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic

Zhen Dong1,2,3,4, Hugo Sepulveda1,2,3,4,5, Leo J Arteaga-Vazquez1

  • 1Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.

Proceedings of the National Academy of Sciences of the United States of America
|January 3, 2025
PubMed

Insights

Mutations in ASXL1, common in clonal hematopoiesis, disrupt heterochromatin by reducing key histone marks. This leads to increased transposable element expression and inflammation-associated genes, impacting health.

Area of Science:

  • Epigenetics and Gene Regulation
  • Hematopoiesis and Cancer Biology
  • Molecular Mechanisms of Disease

Background:

  • Age-related clonal hematopoiesis (CH) involves mutations in genes like ASXL1, DNMT3A, and TET2, and is linked to myeloid malignancies and mortality.
  • While DNMT3A and TET2 roles in DNA methylation are known, the mechanisms linking ASXL1 mutations to CH are unclear.
  • ASXL1 mutations lead to truncated proteins that enhance the PR-DUB complex's deubiquitinase activity, affecting H2AK119Ub levels.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which mutant ASXL1 contributes to clonal hematopoiesis.
  • To investigate the impact of ASXL1 mutations on heterochromatin integrity and gene expression.
  • To explore the link between ASXL1-driven epigenetic changes and associated pathologies.

Main Methods:

  • Analysis of ASXL1 mutant protein interactions with histone methyltransferase complexes (EHMT1-EHMT2).
  • Genome-wide assessment of histone modifications (H3K9me2, H3K9me3, H2AK119Ub) in mouse models (Asxl1tm/+ mice) and human samples (CMML patients).
  • Quantification of transposable element (TE) and satellite repeat expression, and nearby gene expression, including interferon-inducible genes (ISGs).

Main Results:

  • ASXL1 mutant proteins interact with EHMT1-EHMT2, impacting H3K9me1/me2 generation.
  • Myeloid cells from old Asxl1tm/+ mice show genome-wide decreases in H3K9me2, H3K9me3, and H2AK119Ub.
  • Increased TE and satellite repeat expression, and elevated ISG expression, were observed in mutant mice and CMML patients.

Conclusions:

  • Mutant ASXL1 compromises heterochromatin integrity (both constitutive and facultative) in an age-dependent manner by reducing H3K9me2/3 and H2AK119Ub.
  • Reduced heterochromatin marks lead to increased expression of transposable elements and satellite repeats.
  • This aberrant gene expression, particularly of ISGs, may contribute to the inflammatory and malignant phenotypes associated with CH and CMML.

Keywords:
CMMLEHMT1/2 (GLP/G9a)clonal hematopoiesisheterochromatinpolycomb response-deubiquitinase (PR-DUB) complex

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