Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate

Aria L. Byrd; Xufeng Qu; Alexsandr Lukyanchuk; Jinpeng Liu; Fan Chen; Kassandra J. Naughton; Tanner J. DuCote; Xiulong Song; Hannah C. Bowman; Yanming Zhao; Abigail R. Edgin; Chi Wang; Jinze Liu; Christine Fillmore Brainson

doi:10.1016/j.stemcr.2022.11.009

Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate

Aria L. Byrd, Xufeng Qu, Alexsandr Lukyanchuk, Jinpeng Liu, Fan Chen, Kassandra J. Naughton, Tanner J. DuCote, Xiulong Song, Hannah C. Bowman, Yanming Zhao, Abigail R. Edgin, Chi Wang, Jinze Liu, Christine Fillmore Brainson

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

1 Scopus citations

Abstract

Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self-renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of in vivo models revealed that heterozygosity of Ezh2 in mice with ovalbumin-induced lung inflammation led to epithelial cell differentiation patterns similar to those in COPD lung. We also identified cystathionine-β-synthase as a possible upstream factor for PRC2 destabilization. Our findings suggest that PRC2 is integral to facilitating proper lung stem cell differentiation in humans and mice.

Original language	English
Pages (from-to)	289-304
Number of pages	16
Journal	Stem Cell Reports
Volume	18
Issue number	1
DOIs	https://doi.org/10.1016/j.stemcr.2022.11.009
State	Published - Jan 10 2023

Bibliographical note

Funding Information:
We thank Drs. Doug Harrison and Jim Begley at the University of Kentucky A&S Imaging Center for preparation of the scRNA-seq samples. This work was supported in part by NCI K22 CA201036, Kentucky Lung Cancer Research Program, V Foundation Scholar Award, American Cancer Society grants IRG-85-001-25 and 133123-RSG-19-081-01-TBG, NIGMS P20 GM121327, NCI R01 CA237643, Molecular Mechanisms of Toxicity training grant T32ES07266, and Ruth L. Kirschstein National Research Service Award (NRSA) 5F31HL151111. This research was also supported by the Biostatistics & Bioinformatics Shared Resource Facility, Oncogenomics Shared Resource Facility, Biospecimen Procurement & Translational Pathology Shared Resource Facility, and Flow Cytometry & Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30 CA177558). We thank Donna Gilbreath from the Markey Cancer Center Research Communications Office for graphic designs. The authors declare no competing interests.

Funding Information:
We thank Drs. Doug Harrison and Jim Begley at the University of Kentucky A&S Imaging Center for preparation of the scRNA-seq samples. This work was supported in part by NCI K22 CA201036 , Kentucky Lung Cancer Research Program, V Foundation Scholar Award, American Cancer Society grants IRG-85-001-25 and 133123-RSG-19-081-01-TBG , NIGMS P20 GM121327 , NCI R01 CA237643 , Molecular Mechanisms of Toxicity training grant T32ES07266 , and Ruth L. Kirschstein National Research Service Award ( NRSA ) 5F31HL151111 . This research was also supported by the Biostatistics & Bioinformatics Shared Resource Facility, Oncogenomics Shared Resource Facility, Biospecimen Procurement & Translational Pathology Shared Resource Facility, and Flow Cytometry & Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center ( P30 CA177558 ). We thank Donna Gilbreath from the Markey Cancer Center Research Communications Office for graphic designs.

Publisher Copyright:
© 2022 The Author(s)

Keywords

Polycomb Repressive Complex
chronic obstructive pulmonary disease
lung stem cells
organoids

ASJC Scopus subject areas

Biochemistry
Genetics
Developmental Biology
Cell Biology

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10.1016/j.stemcr.2022.11.009

Cite this

Byrd, A. L., Qu, X., Lukyanchuk, A., Liu, J., Chen, F., Naughton, K. J., DuCote, T. J., Song, X., Bowman, H. C., Zhao, Y., Edgin, A. R., Wang, C., Liu, J., & Brainson, C. F. (2023). Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate. Stem Cell Reports, 18(1), 289-304. https://doi.org/10.1016/j.stemcr.2022.11.009

@article{efa2c96ecf9d4cdaa7cce8018e63d92b,

title = "Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate",

abstract = "Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self-renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of in vivo models revealed that heterozygosity of Ezh2 in mice with ovalbumin-induced lung inflammation led to epithelial cell differentiation patterns similar to those in COPD lung. We also identified cystathionine-β-synthase as a possible upstream factor for PRC2 destabilization. Our findings suggest that PRC2 is integral to facilitating proper lung stem cell differentiation in humans and mice.",

keywords = "Polycomb Repressive Complex, chronic obstructive pulmonary disease, lung stem cells, organoids",

author = "Byrd, {Aria L.} and Xufeng Qu and Alexsandr Lukyanchuk and Jinpeng Liu and Fan Chen and Naughton, {Kassandra J.} and DuCote, {Tanner J.} and Xiulong Song and Bowman, {Hannah C.} and Yanming Zhao and Edgin, {Abigail R.} and Chi Wang and Jinze Liu and Brainson, {Christine Fillmore}",

note = "Funding Information: We thank Drs. Doug Harrison and Jim Begley at the University of Kentucky A&S Imaging Center for preparation of the scRNA-seq samples. This work was supported in part by NCI K22 CA201036, Kentucky Lung Cancer Research Program, V Foundation Scholar Award, American Cancer Society grants IRG-85-001-25 and 133123-RSG-19-081-01-TBG, NIGMS P20 GM121327, NCI R01 CA237643, Molecular Mechanisms of Toxicity training grant T32ES07266, and Ruth L. Kirschstein National Research Service Award (NRSA) 5F31HL151111. This research was also supported by the Biostatistics & Bioinformatics Shared Resource Facility, Oncogenomics Shared Resource Facility, Biospecimen Procurement & Translational Pathology Shared Resource Facility, and Flow Cytometry & Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30 CA177558). We thank Donna Gilbreath from the Markey Cancer Center Research Communications Office for graphic designs. The authors declare no competing interests. Funding Information: We thank Drs. Doug Harrison and Jim Begley at the University of Kentucky A&S Imaging Center for preparation of the scRNA-seq samples. This work was supported in part by NCI K22 CA201036 , Kentucky Lung Cancer Research Program, V Foundation Scholar Award, American Cancer Society grants IRG-85-001-25 and 133123-RSG-19-081-01-TBG , NIGMS P20 GM121327 , NCI R01 CA237643 , Molecular Mechanisms of Toxicity training grant T32ES07266 , and Ruth L. Kirschstein National Research Service Award ( NRSA ) 5F31HL151111 . This research was also supported by the Biostatistics & Bioinformatics Shared Resource Facility, Oncogenomics Shared Resource Facility, Biospecimen Procurement & Translational Pathology Shared Resource Facility, and Flow Cytometry & Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center ( P30 CA177558 ). We thank Donna Gilbreath from the Markey Cancer Center Research Communications Office for graphic designs. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

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doi = "10.1016/j.stemcr.2022.11.009",

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Byrd, AL, Qu, X, Lukyanchuk, A, Liu, J, Chen, F, Naughton, KJ, DuCote, TJ, Song, X, Bowman, HC, Zhao, Y, Edgin, AR, Wang, C, Liu, J & Brainson, CF 2023, 'Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate', Stem Cell Reports, vol. 18, no. 1, pp. 289-304. https://doi.org/10.1016/j.stemcr.2022.11.009

TY - JOUR

T1 - Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate

AU - Byrd, Aria L.

AU - Qu, Xufeng

AU - Lukyanchuk, Alexsandr

AU - Liu, Jinpeng

AU - Chen, Fan

AU - Naughton, Kassandra J.

AU - DuCote, Tanner J.

AU - Song, Xiulong

AU - Bowman, Hannah C.

AU - Zhao, Yanming

AU - Edgin, Abigail R.

AU - Wang, Chi

AU - Liu, Jinze

AU - Brainson, Christine Fillmore

N1 - Funding Information: We thank Drs. Doug Harrison and Jim Begley at the University of Kentucky A&S Imaging Center for preparation of the scRNA-seq samples. This work was supported in part by NCI K22 CA201036, Kentucky Lung Cancer Research Program, V Foundation Scholar Award, American Cancer Society grants IRG-85-001-25 and 133123-RSG-19-081-01-TBG, NIGMS P20 GM121327, NCI R01 CA237643, Molecular Mechanisms of Toxicity training grant T32ES07266, and Ruth L. Kirschstein National Research Service Award (NRSA) 5F31HL151111. This research was also supported by the Biostatistics & Bioinformatics Shared Resource Facility, Oncogenomics Shared Resource Facility, Biospecimen Procurement & Translational Pathology Shared Resource Facility, and Flow Cytometry & Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30 CA177558). We thank Donna Gilbreath from the Markey Cancer Center Research Communications Office for graphic designs. The authors declare no competing interests. Funding Information: We thank Drs. Doug Harrison and Jim Begley at the University of Kentucky A&S Imaging Center for preparation of the scRNA-seq samples. This work was supported in part by NCI K22 CA201036 , Kentucky Lung Cancer Research Program, V Foundation Scholar Award, American Cancer Society grants IRG-85-001-25 and 133123-RSG-19-081-01-TBG , NIGMS P20 GM121327 , NCI R01 CA237643 , Molecular Mechanisms of Toxicity training grant T32ES07266 , and Ruth L. Kirschstein National Research Service Award ( NRSA ) 5F31HL151111 . This research was also supported by the Biostatistics & Bioinformatics Shared Resource Facility, Oncogenomics Shared Resource Facility, Biospecimen Procurement & Translational Pathology Shared Resource Facility, and Flow Cytometry & Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center ( P30 CA177558 ). We thank Donna Gilbreath from the Markey Cancer Center Research Communications Office for graphic designs. Publisher Copyright: © 2022 The Author(s)

PY - 2023/1/10

Y1 - 2023/1/10

N2 - Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self-renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of in vivo models revealed that heterozygosity of Ezh2 in mice with ovalbumin-induced lung inflammation led to epithelial cell differentiation patterns similar to those in COPD lung. We also identified cystathionine-β-synthase as a possible upstream factor for PRC2 destabilization. Our findings suggest that PRC2 is integral to facilitating proper lung stem cell differentiation in humans and mice.

AB - Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self-renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of in vivo models revealed that heterozygosity of Ezh2 in mice with ovalbumin-induced lung inflammation led to epithelial cell differentiation patterns similar to those in COPD lung. We also identified cystathionine-β-synthase as a possible upstream factor for PRC2 destabilization. Our findings suggest that PRC2 is integral to facilitating proper lung stem cell differentiation in humans and mice.

KW - Polycomb Repressive Complex

KW - chronic obstructive pulmonary disease

KW - lung stem cells

KW - organoids

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UR - http://www.scopus.com/inward/citedby.url?scp=85146193310&partnerID=8YFLogxK

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ER -

Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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