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

Authors

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

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-b-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.

Document Type

Article

Publication Date

1-2023

Notes/Citation Information

ª 2022 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.stemcr.2022.11.009

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 Com- munications Office for graphic designs.

Repository Citation

Byrd, Aria; Qu, Xufeng; Lukyanchuk, Alexsandr; Liu, Jinpeng; Chen, Fan; Naughton, Kassandra J.; DuCote, Tanner; Song, Xiulong; Bowman, Hannah; Zhao, Yanming; Edgin, Abigail R; Wang, Chi; Liu, Jinze; and Brainson, Christine Fillmore, "Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate" (2023). Markey Cancer Center Faculty Publications. 326.
https://uknowledge.uky.edu/markey_facpub/326