STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia

Alexander Fischer; Benjamin Hernandez-Rodriguez; Roger Mulet-Lazaro; Margit Nuetzel; Fabian Hoelzl; Stanley van Herk; Francois G. Kavelaars; Hanna Stanewsky; Ute Ackermann; Amadou H. Niang; Noelia Diaz; Edith Reuschel; Nicholas Strieder; Inmaculada Hernandez-Lopez; Peter J. M. Valk; Juan M. Vaquerizas; Michael Rehli; Ruud Delwel; Claudia Gebhard

doi:10.1016/j.celrep.2024.114498

STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia

Alexander Fischer, Benjamin Hernandez-Rodriguez, Roger Mulet-Lazaro, Margit Nuetzel, Fabian Hoelzl, Stanley van Herk, Francois G. Kavelaars, Hanna Stanewsky, Ute Ackermann, Amadou H. Niang, Noelia Diaz, Edith Reuschel, Nicholas Strieder, Inmaculada Hernandez-Lopez, Peter J. M. Valk, Juan M. Vaquerizas, Michael Rehli, Ruud Delwel, Claudia Gebhard^*

^*Corresponding author for this work

Hematology

Research output: Contribution to journal › Article › Academic › peer-review

3 Citations (Scopus)

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.

Original language	English
Article number	114498
Number of pages	30
Journal	Cell Reports
Volume	43
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2024.114498
Publication status	Published - 27 Aug 2024

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© 2024 The Authors

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Fischer, A., Hernandez-Rodriguez, B., Mulet-Lazaro, R., Nuetzel, M., Hoelzl, F., van Herk, S., Kavelaars, F. G., Stanewsky, H., Ackermann, U., Niang, A. H., Diaz, N., Reuschel, E., Strieder, N., Hernandez-Lopez, I., Valk, P. J. M., Vaquerizas, J. M., Rehli, M., Delwel, R., & Gebhard, C. (2024). STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia. Cell Reports, 43(8), Article 114498. https://doi.org/10.1016/j.celrep.2024.114498

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title = "STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia",

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.",

author = "Alexander Fischer and Benjamin Hernandez-Rodriguez and Roger Mulet-Lazaro and Margit Nuetzel and Fabian Hoelzl and {van Herk}, Stanley and Kavelaars, {Francois G.} and Hanna Stanewsky and Ute Ackermann and Niang, {Amadou H.} and Noelia Diaz and Edith Reuschel and Nicholas Strieder and Inmaculada Hernandez-Lopez and Valk, {Peter J. M.} and Vaquerizas, {Juan M.} and Michael Rehli and Ruud Delwel and Claudia Gebhard",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = aug,

day = "27",

doi = "10.1016/j.celrep.2024.114498",

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Fischer, A, Hernandez-Rodriguez, B, Mulet-Lazaro, R, Nuetzel, M, Hoelzl, F, van Herk, S , Kavelaars, FG, Stanewsky, H, Ackermann, U, Niang, AH, Diaz, N, Reuschel, E, Strieder, N, Hernandez-Lopez, I, Valk, PJM, Vaquerizas, JM, Rehli, M, Delwel, R & Gebhard, C 2024, 'STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia', Cell Reports, vol. 43, no. 8, 114498. https://doi.org/10.1016/j.celrep.2024.114498

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T1 - STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia

AU - Fischer, Alexander

AU - Hernandez-Rodriguez, Benjamin

AU - Mulet-Lazaro, Roger

AU - Nuetzel, Margit

AU - Hoelzl, Fabian

AU - van Herk, Stanley

AU - Kavelaars, Francois G.

AU - Stanewsky, Hanna

AU - Ackermann, Ute

AU - Niang, Amadou H.

AU - Diaz, Noelia

AU - Reuschel, Edith

AU - Strieder, Nicholas

AU - Hernandez-Lopez, Inmaculada

AU - Valk, Peter J. M.

AU - Vaquerizas, Juan M.

AU - Rehli, Michael

AU - Delwel, Ruud

AU - Gebhard, Claudia

PY - 2024/8/27

Y1 - 2024/8/27

N2 - 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.

AB - 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.

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DO - 10.1016/j.celrep.2024.114498

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JO - Cell Reports

JF - Cell Reports

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M1 - 114498

ER -

STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia

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