Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling

Cemre Celen; Jen Chieh Chuang; Shunli Shen; Lin Li; Gianna Maggiore; Yuemeng Jia; Xin Luo; Austin Moore; Yunguan Wang; Jordan E. Otto; Clayton K. Collings; Zixi Wang; Xuxu Sun; Ibrahim Nassour; Jiyoung Park; Alexandra Ghaben; Tao Wang; Sam C. Wang; Philipp E. Scherer; Cigall Kadoch; Hao Zhu

doi:10.1016/j.celrep.2022.111581

Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling

Cemre Celen, Jen Chieh Chuang, Shunli Shen, Lin Li, Gianna Maggiore, Yuemeng Jia, Xin Luo, Austin Moore, Yunguan Wang, Jordan E. Otto, Clayton K. Collings, Zixi Wang, Xuxu Sun, Ibrahim Nassour, Jiyoung Park, Alexandra Ghaben, Tao Wang, Sam C. Wang, Philipp E. Scherer, Cigall KadochHao Zhu

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

Abstract

The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice are protected against streptozotocin-induced diabetes. Cell-type and temporally specific genetic dissection show that β-cell-specific Arid1a deletion can potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets reveal increased neuregulin-ERBB-NR4A signaling. Chemical inhibition of ERBB or NR4A1 blocks increased regeneration associated with Arid1a loss. Mammalian SWI/SNF (mSWI/SNF) complex activity is a barrier to β-cell regeneration in physiologic and disease states.

Original language	English (US)
Article number	111581
Journal	Cell Reports
Volume	41
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2022.111581
State	Published - Nov 1 2022

Keywords

Arid1a
CP: Cell biology
CP: Developmental biology
EGFR/ERBB
NR4A nuclear receptors
NRG/EGF signaling
SWI/SNF
chromatin remodeling
diabetes
islets
β-cell regeneration

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.111581

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Celen, C., Chuang, J. C., Shen, S., Li, L., Maggiore, G., Jia, Y., Luo, X., Moore, A., Wang, Y., Otto, J. E., Collings, C. K., Wang, Z., Sun, X., Nassour, I., Park, J., Ghaben, A., Wang, T., Wang, S. C., Scherer, P. E., ... Zhu, H. (2022). Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling. Cell Reports, 41(5), Article 111581. https://doi.org/10.1016/j.celrep.2022.111581

Celen, C, Chuang, JC, Shen, S, Li, L, Maggiore, G, Jia, Y, Luo, X, Moore, A, Wang, Y, Otto, JE, Collings, CK, Wang, Z, Sun, X, Nassour, I, Park, J, Ghaben, A, Wang, T , Wang, SC , Scherer, PE, Kadoch, C & Zhu, H 2022, 'Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling', Cell Reports, vol. 41, no. 5, 111581. https://doi.org/10.1016/j.celrep.2022.111581

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title = "Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling",

abstract = "The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice are protected against streptozotocin-induced diabetes. Cell-type and temporally specific genetic dissection show that β-cell-specific Arid1a deletion can potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets reveal increased neuregulin-ERBB-NR4A signaling. Chemical inhibition of ERBB or NR4A1 blocks increased regeneration associated with Arid1a loss. Mammalian SWI/SNF (mSWI/SNF) complex activity is a barrier to β-cell regeneration in physiologic and disease states.",

keywords = "Arid1a, CP: Cell biology, CP: Developmental biology, EGFR/ERBB, NR4A nuclear receptors, NRG/EGF signaling, SWI/SNF, chromatin remodeling, diabetes, islets, β-cell regeneration",

author = "Cemre Celen and Chuang, {Jen Chieh} and Shunli Shen and Lin Li and Gianna Maggiore and Yuemeng Jia and Xin Luo and Austin Moore and Yunguan Wang and Otto, {Jordan E.} and Collings, {Clayton K.} and Zixi Wang and Xuxu Sun and Ibrahim Nassour and Jiyoung Park and Alexandra Ghaben and Tao Wang and Wang, {Sam C.} and Scherer, {Philipp E.} and Cigall Kadoch and Hao Zhu",

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doi = "10.1016/j.celrep.2022.111581",

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T1 - Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling

AU - Celen, Cemre

AU - Chuang, Jen Chieh

AU - Shen, Shunli

AU - Li, Lin

AU - Maggiore, Gianna

AU - Jia, Yuemeng

AU - Luo, Xin

AU - Moore, Austin

AU - Wang, Yunguan

AU - Otto, Jordan E.

AU - Collings, Clayton K.

AU - Wang, Zixi

AU - Sun, Xuxu

AU - Nassour, Ibrahim

AU - Park, Jiyoung

AU - Ghaben, Alexandra

AU - Wang, Tao

AU - Wang, Sam C.

AU - Scherer, Philipp E.

AU - Kadoch, Cigall

AU - Zhu, Hao

PY - 2022/11/1

Y1 - 2022/11/1

N2 - The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice are protected against streptozotocin-induced diabetes. Cell-type and temporally specific genetic dissection show that β-cell-specific Arid1a deletion can potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets reveal increased neuregulin-ERBB-NR4A signaling. Chemical inhibition of ERBB or NR4A1 blocks increased regeneration associated with Arid1a loss. Mammalian SWI/SNF (mSWI/SNF) complex activity is a barrier to β-cell regeneration in physiologic and disease states.

AB - The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice are protected against streptozotocin-induced diabetes. Cell-type and temporally specific genetic dissection show that β-cell-specific Arid1a deletion can potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets reveal increased neuregulin-ERBB-NR4A signaling. Chemical inhibition of ERBB or NR4A1 blocks increased regeneration associated with Arid1a loss. Mammalian SWI/SNF (mSWI/SNF) complex activity is a barrier to β-cell regeneration in physiologic and disease states.

KW - Arid1a

KW - CP: Cell biology

KW - CP: Developmental biology

KW - EGFR/ERBB

KW - NR4A nuclear receptors

KW - NRG/EGF signaling

KW - SWI/SNF

KW - chromatin remodeling

KW - diabetes

KW - islets

KW - β-cell regeneration

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DO - 10.1016/j.celrep.2022.111581

M3 - Article

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SN - 2211-1247

VL - 41

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 111581

ER -

Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling

Abstract

Keywords

ASJC Scopus subject areas

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