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Three-dimensional Genome Organization Maps in Normal Haematopoietic Stem Cells and Acute Myeloid Leukemia

Benny Wang, Lingshi Kong, View ORCID ProfileDeepak Babu, Ruchi Choudhary, Winnie Fam, Jia Qi Tng, Yufen Goh, Bertrand Wong Jern Han, Xin Liu, Fang Fang Song, Priscella Chia, Ming Chun Chan, View ORCID ProfileOmer An, Cheng Yong Tham, View ORCID ProfileTouati Benoukraf, Henry Yang, Wilson Wang, Wee Joo Chng, Daniel Tenen, View ORCID ProfileMelissa Jane Fullwood
doi: https://doi.org/10.1101/2020.04.18.047738
Benny Wang
1School of Biological Sciences, Nanyang Technological University
2Cancer Science Institute of Singapore, National University of Singapore
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Lingshi Kong
1School of Biological Sciences, Nanyang Technological University
2Cancer Science Institute of Singapore, National University of Singapore
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Deepak Babu
2Cancer Science Institute of Singapore, National University of Singapore
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Ruchi Choudhary
1School of Biological Sciences, Nanyang Technological University
2Cancer Science Institute of Singapore, National University of Singapore
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Winnie Fam
2Cancer Science Institute of Singapore, National University of Singapore
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Jia Qi Tng
2Cancer Science Institute of Singapore, National University of Singapore
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Yufen Goh
2Cancer Science Institute of Singapore, National University of Singapore
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Bertrand Wong Jern Han
1School of Biological Sciences, Nanyang Technological University
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Xin Liu
3National University Cancer Institute, National University Health System
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Fang Fang Song
3National University Cancer Institute, National University Health System
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Priscella Chia
3National University Cancer Institute, National University Health System
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Ming Chun Chan
4Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore
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Omer An
2Cancer Science Institute of Singapore, National University of Singapore
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Cheng Yong Tham
2Cancer Science Institute of Singapore, National University of Singapore
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Touati Benoukraf
2Cancer Science Institute of Singapore, National University of Singapore
5Memorial University of Newfoundland
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Henry Yang
2Cancer Science Institute of Singapore, National University of Singapore
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Wilson Wang
4Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore
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Wee Joo Chng
2Cancer Science Institute of Singapore, National University of Singapore
3National University Cancer Institute, National University Health System
6Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
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Daniel Tenen
2Cancer Science Institute of Singapore, National University of Singapore
7Harvard Stem Cell Institute, Boston
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Melissa Jane Fullwood
1School of Biological Sciences, Nanyang Technological University
2Cancer Science Institute of Singapore, National University of Singapore
8Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
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  • ORCID record for Melissa Jane Fullwood
  • For correspondence: mfullwood@ntu.edu.sg
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Abstract

Acute Myeloid Leukemia (AML) is a highly lethal blood cancer arising due to aberrant differentiation of haematopoietic stem cells. Here we obtained 3D genome organization maps by Hi-C in the CD34+ haematopoietic stem cells from three healthy individuals and eight individuals with AML, and found that AML have increased loops to oncogenes compared with normal CD34+ cells. The MEIS1 oncogenic transcription factor is regulated by a Frequently Interacting Region (FIRE). This FIRE is only present in normal bone marrow samples, and four of eight AML sample. FIRE presence is associated with MEIS1 expression. CRISPR excision of a FIRE boundary led to loss of MEIS1 and reduced cell growth. Moreover, MEIS1 can bind to the promoter of HOXA9, and HOXA9 shows gain of Acute Myeloid Leukemia-specific super-enhancers that loop to the HOXA9 promoter.

Significance We found that Acute Myeloid Leukemias have more chromatin loops to oncogenes compared with normal blood stem cells. We identified heterogeneity in chromatin interactions at oncogenes, and heterogeneity in super-enhancers that loop to oncogenes, as two key epigenetic mechanisms that underlie MEIS1 and HOXA9 oncogene expression respectively.

Competing Interest Statement

M.J.F declares two patents on methodologies related to ChIA-PET. No other conflicts of interest are declared.

Footnotes

  • ↵* Co-first authors

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 06, 2021.
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Three-dimensional Genome Organization Maps in Normal Haematopoietic Stem Cells and Acute Myeloid Leukemia
Benny Wang, Lingshi Kong, Deepak Babu, Ruchi Choudhary, Winnie Fam, Jia Qi Tng, Yufen Goh, Bertrand Wong Jern Han, Xin Liu, Fang Fang Song, Priscella Chia, Ming Chun Chan, Omer An, Cheng Yong Tham, Touati Benoukraf, Henry Yang, Wilson Wang, Wee Joo Chng, Daniel Tenen, Melissa Jane Fullwood
bioRxiv 2020.04.18.047738; doi: https://doi.org/10.1101/2020.04.18.047738
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Three-dimensional Genome Organization Maps in Normal Haematopoietic Stem Cells and Acute Myeloid Leukemia
Benny Wang, Lingshi Kong, Deepak Babu, Ruchi Choudhary, Winnie Fam, Jia Qi Tng, Yufen Goh, Bertrand Wong Jern Han, Xin Liu, Fang Fang Song, Priscella Chia, Ming Chun Chan, Omer An, Cheng Yong Tham, Touati Benoukraf, Henry Yang, Wilson Wang, Wee Joo Chng, Daniel Tenen, Melissa Jane Fullwood
bioRxiv 2020.04.18.047738; doi: https://doi.org/10.1101/2020.04.18.047738

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