1. STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia.
- Author
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Fischer A, Hernández-Rodríguez B, Mulet-Lazaro R, Nuetzel M, Hölzl F, van Herk S, Kavelaars FG, Stanewsky H, Ackermann U, Niang AH, Diaz N, Reuschel E, Strieder N, Hernández-López I, Valk PJM, Vaquerizas JM, Rehli M, Delwel R, and Gebhard C
- Subjects
- Humans, Hematopoietic Stem Cells metabolism, Cell Differentiation genetics, Gene Expression Regulation, Leukemic, Antigens, Nuclear metabolism, Antigens, Nuclear genetics, Nuclear Proteins, Cohesins, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute metabolism, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Chromatin metabolism, Chromosomal Proteins, Non-Histone metabolism, Chromosomal Proteins, Non-Histone genetics, Mutation genetics
- Abstract
Cohesin shapes the chromatin architecture, including enhancer-promoter interactions. Its components, especially STAG2, but not its paralog STAG1, are frequently mutated in myeloid malignancies. To elucidate the underlying mechanisms of leukemogenesis, we comprehensively characterized genetic, transcriptional, and chromatin conformational changes in acute myeloid leukemia (AML) patient samples. Specific loci displayed altered cohesin occupancy, gene expression, and local chromatin activation, which were not compensated by the remaining STAG1-cohesin. These changes could be linked to disrupted spatial chromatin looping in cohesin-mutated AMLs. Complementary depletion of STAG2 or STAG1 in primary human hematopoietic progenitors (HSPCs) revealed effects resembling STAG2-mutant AML-specific changes following STAG2 knockdown, not invoked by the depletion of STAG1. STAG2-deficient HSPCs displayed impaired differentiation capacity and maintained HSPC-like gene expression. This work establishes STAG2 as a key regulator of chromatin contacts, gene expression, and differentiation in the hematopoietic system and identifies candidate target genes that may be implicated in human leukemogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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