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Integrated genomic analysis of AgRP neurons reveals that IRF3 regulates leptin’s hunger-suppressing effects

View ORCID ProfileFrankie D. Heyward, Nan Liu, Christopher Jacobs, Rachael Ivison, Natalia Machado, Aykut Uner, Harini Srinivasan, Suraj J. Patel, Anton Gulko, Tyler Sermersheim, Stuart H. Orkin, Linus Tsai, Evan D. Rosen
doi: https://doi.org/10.1101/2022.01.03.474708
Frankie D. Heyward
1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center
8Broad Institute of Harvard and MIT
9Harvard Medical School
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  • ORCID record for Frankie D. Heyward
  • For correspondence: erosen@bidmc.harvard.edu fheyward@bidmc.harvard.edu
Nan Liu
2Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital
4Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China
5Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
9Harvard Medical School
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Christopher Jacobs
1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center
8Broad Institute of Harvard and MIT
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Rachael Ivison
1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center
8Broad Institute of Harvard and MIT
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Natalia Machado
6Department of Neurology, Beth Israel Deaconess Medical Center
9Harvard Medical School
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Aykut Uner
1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center
9Harvard Medical School
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Harini Srinivasan
1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center
8Broad Institute of Harvard and MIT
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Suraj J. Patel
7Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center
9Harvard Medical School
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Anton Gulko
1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center
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Tyler Sermersheim
1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center
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Stuart H. Orkin
2Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital
3Howard Hughes Medical Institute, Boston, MA, USA
9Harvard Medical School
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Linus Tsai
1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center
8Broad Institute of Harvard and MIT
9Harvard Medical School
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Evan D. Rosen
1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center
8Broad Institute of Harvard and MIT
9Harvard Medical School
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  • For correspondence: erosen@bidmc.harvard.edu fheyward@bidmc.harvard.edu
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ABSTRACT

AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles during opposing states of fasting-induced hunger and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 28 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons, while live-cell imaging in vitro indicate that leptin can activate neuronal IRF3 in a cell autonomous manner. Finally, we employ CUT&RUN to uncover direct transcriptional targets of IRF3 in AgRP neurons in vivo. Thus, our findings identify AgRP neuron-expressed IRF3 as a key transcriptional effector of the hunger-suppressing effects of leptin.

Competing Interest Statement

The authors have declared no competing interest.

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 January 03, 2022.
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Integrated genomic analysis of AgRP neurons reveals that IRF3 regulates leptin’s hunger-suppressing effects
Frankie D. Heyward, Nan Liu, Christopher Jacobs, Rachael Ivison, Natalia Machado, Aykut Uner, Harini Srinivasan, Suraj J. Patel, Anton Gulko, Tyler Sermersheim, Stuart H. Orkin, Linus Tsai, Evan D. Rosen
bioRxiv 2022.01.03.474708; doi: https://doi.org/10.1101/2022.01.03.474708
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Integrated genomic analysis of AgRP neurons reveals that IRF3 regulates leptin’s hunger-suppressing effects
Frankie D. Heyward, Nan Liu, Christopher Jacobs, Rachael Ivison, Natalia Machado, Aykut Uner, Harini Srinivasan, Suraj J. Patel, Anton Gulko, Tyler Sermersheim, Stuart H. Orkin, Linus Tsai, Evan D. Rosen
bioRxiv 2022.01.03.474708; doi: https://doi.org/10.1101/2022.01.03.474708

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