RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPα- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction

Anetta Ptasinska; Anna Pickin; Salam A. Assi; Paulynn Suyin Chin; Luke Ames; Roberto Avellino; Stephan Gröschel; Ruud Delwel; Peter N. Cockerill; Cameron S. Osborne; Constanze Bonifer

doi:10.1016/j.celrep.2019.08.040

RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPα- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction

Anetta Ptasinska, Anna Pickin, Salam A. Assi, Paulynn Suyin Chin, Luke Ames, Roberto Avellino, Stephan Gröschel, Ruud Delwel, Peter N. Cockerill, Cameron S. Osborne, Constanze Bonifer^*

^*Corresponding author for this work

Medical & Molecular Genetics

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

21 Citations (Scopus)

Abstract

Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the RUNX1-ETO fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed that the maintenance of t(8;21) AML is dependent on RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well as gene expression, and initiates myeloid differentiation. However, how these processes are connected within a gene regulatory network is unclear. To address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements to their respective genes. To construct a RUNX1-ETO-dependent gene regulatory network maintaining AML, we integrated cis-regulatory element interactions with gene expression and transcription factor binding data. This analysis shows that RUNX1-ETO participates in cis-regulatory element interactions. However, differential interactions following RUNX1-ETO depletion are driven by alterations in the binding of RUNX1-ETO-regulated transcription factors.

Original language	English
Pages (from-to)	3022-3031.e7
Journal	Cell Reports
Volume	28
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2019.08.040
Publication status	Published - 17 Sept 2019

Keywords

acute myeloid leukemia
AP-1 signaling in acute myeloid leukemia
chromatin programming
epigenetic regulation
integrated analysis of high-throughput data
Promoter-Capture Hi-C
promoter-enhancer interactions
RUNX1-ETO
transcription factors
transcriptional networks

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2019.08.040

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@article{c3181e3398494d8db70ce25a905ad56c,

title = "RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPα- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction",

abstract = "Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the RUNX1-ETO fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed that the maintenance of t(8;21) AML is dependent on RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well as gene expression, and initiates myeloid differentiation. However, how these processes are connected within a gene regulatory network is unclear. To address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements to their respective genes. To construct a RUNX1-ETO-dependent gene regulatory network maintaining AML, we integrated cis-regulatory element interactions with gene expression and transcription factor binding data. This analysis shows that RUNX1-ETO participates in cis-regulatory element interactions. However, differential interactions following RUNX1-ETO depletion are driven by alterations in the binding of RUNX1-ETO-regulated transcription factors.",

keywords = "acute myeloid leukemia, AP-1 signaling in acute myeloid leukemia, chromatin programming, epigenetic regulation, integrated analysis of high-throughput data, Promoter-Capture Hi-C, promoter-enhancer interactions, RUNX1-ETO, transcription factors, transcriptional networks",

author = "Anetta Ptasinska and Anna Pickin and Assi, {Salam A.} and Chin, {Paulynn Suyin} and Luke Ames and Roberto Avellino and Stephan Gr{\"o}schel and Ruud Delwel and Cockerill, {Peter N.} and Osborne, {Cameron S.} and Constanze Bonifer",

year = "2019",

month = sep,

day = "17",

doi = "10.1016/j.celrep.2019.08.040",

language = "English",

volume = "28",

pages = "3022--3031.e7",

journal = "Cell Reports",

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number = "12",

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TY - JOUR

T1 - RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPα- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction

AU - Ptasinska, Anetta

AU - Pickin, Anna

AU - Assi, Salam A.

AU - Chin, Paulynn Suyin

AU - Ames, Luke

AU - Avellino, Roberto

AU - Gröschel, Stephan

AU - Delwel, Ruud

AU - Cockerill, Peter N.

AU - Osborne, Cameron S.

AU - Bonifer, Constanze

PY - 2019/9/17

Y1 - 2019/9/17

N2 - Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the RUNX1-ETO fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed that the maintenance of t(8;21) AML is dependent on RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well as gene expression, and initiates myeloid differentiation. However, how these processes are connected within a gene regulatory network is unclear. To address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements to their respective genes. To construct a RUNX1-ETO-dependent gene regulatory network maintaining AML, we integrated cis-regulatory element interactions with gene expression and transcription factor binding data. This analysis shows that RUNX1-ETO participates in cis-regulatory element interactions. However, differential interactions following RUNX1-ETO depletion are driven by alterations in the binding of RUNX1-ETO-regulated transcription factors.

AB - Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the RUNX1-ETO fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed that the maintenance of t(8;21) AML is dependent on RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well as gene expression, and initiates myeloid differentiation. However, how these processes are connected within a gene regulatory network is unclear. To address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements to their respective genes. To construct a RUNX1-ETO-dependent gene regulatory network maintaining AML, we integrated cis-regulatory element interactions with gene expression and transcription factor binding data. This analysis shows that RUNX1-ETO participates in cis-regulatory element interactions. However, differential interactions following RUNX1-ETO depletion are driven by alterations in the binding of RUNX1-ETO-regulated transcription factors.

KW - acute myeloid leukemia

KW - AP-1 signaling in acute myeloid leukemia

KW - chromatin programming

KW - epigenetic regulation

KW - integrated analysis of high-throughput data

KW - Promoter-Capture Hi-C

KW - promoter-enhancer interactions

KW - RUNX1-ETO

KW - transcription factors

KW - transcriptional networks

UR - http://www.scopus.com/inward/record.url?scp=85071724329&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.08.040

DO - 10.1016/j.celrep.2019.08.040

M3 - Article

AN - SCOPUS:85071724329

SN - 2211-1247

VL - 28

SP - 3022-3031.e7

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -

RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPα- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction

Abstract

Keywords

UN SDGs

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