Targeting DNA methylation depletes uterine leiomyoma stem cell-enriched population by stimulatingtheir differentiation

Shimeng Liu; Ping Yin; Jingting Xu; Ariel J. Dotts; Stacy A. Kujawa; John S.V. Coon; Hong Zhao; Ali Shilatifard; Yang Dai; Serdar E. Bulun

doi:10.1210/endocr/bqaa143

Targeting DNA methylation depletes uterine leiomyoma stem cell-enriched population by stimulatingtheir differentiation

Shimeng Liu, Ping Yin, Jingting Xu, Ariel J. Dotts, Stacy A. Kujawa, John S.V. Coon, Hong Zhao, Ali Shilatifard, Yang Dai, Serdar E. Bulun^*

^*Corresponding author for this work

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

19 Scopus citations

Abstract

Uterine leiomyoma (LM) is the most common tumor in women and can cause severe morbidity. Leiomyoma growth requires the maintenance and proliferation of a stem cell population. Dysregulated deoxyribonucleic acid (DNA) methylation has been reported in LM, but its role in LM stem cell regulation remains unclear. Here, we fluorescence-activated cell sorting (FACS)-sorted cells from human LM tissues into 3 populations: LM stem cell-like cells (LSC, 5%), LM intermediate cells (LIC, 7%), and differentiated LM cells (LDC, 88%), and we analyzed the transcriptome and epigenetic landscape of LM cells at different differentiation stages. Leiomyoma stem cell-like cells harbored a unique methylome, with 8862 differentially methylated regions compared to LIC and 9444 compared to LDC, most of which were hypermethylated. Consistent with global hypermethylation, transcript levels of TET1 and TET3 methylcytosine dioxygenases were lower in LSC. Integrative analyses revealed an inverse relationship between methylation and gene expression changes during LSC differentiation. In LSC, hypermethylation suppressed the genes important for myometrium- and LM-associated functions, including muscle contraction and hormone action, to maintain stemness. The hypomethylating drug, 5′-Aza, stimulated LSC differentiation, depleting the stem cell population and inhibiting tumor initiation. Our data suggest that DNA methylation maintains the pool of LSC, which is critical for the regeneration of LM tumors.

Original language	English (US)
Journal	Endocrinology (United States)
Volume	161
Issue number	10
DOIs	https://doi.org/10.1210/endocr/bqaa143
State	Published - Oct 1 2020

Funding

We acknowledge the Northwestern University Flow Cytometry Facility and NUSeq Core, which are co-funded by the National Cancer Institute Cancer Center Grant CA060553. Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system, purchased through the support of NIH 1S10OD011996-01. We thank Drs Jindan Yu and Debu Chakravarti for critical guidance and reading of the manuscript. We are also grateful to Guangyuan Zhao for the technical assistance of data analysis in this manuscript.

Keywords

DNA methylation
Stem cell differentiation
Uterine leiomyoma

ASJC Scopus subject areas

Endocrinology

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10.1210/endocr/bqaa143

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@article{38d24afedb14487289b2b44dcb501ec9,

title = "Targeting DNA methylation depletes uterine leiomyoma stem cell-enriched population by stimulatingtheir differentiation",

abstract = "Uterine leiomyoma (LM) is the most common tumor in women and can cause severe morbidity. Leiomyoma growth requires the maintenance and proliferation of a stem cell population. Dysregulated deoxyribonucleic acid (DNA) methylation has been reported in LM, but its role in LM stem cell regulation remains unclear. Here, we fluorescence-activated cell sorting (FACS)-sorted cells from human LM tissues into 3 populations: LM stem cell-like cells (LSC, 5%), LM intermediate cells (LIC, 7%), and differentiated LM cells (LDC, 88%), and we analyzed the transcriptome and epigenetic landscape of LM cells at different differentiation stages. Leiomyoma stem cell-like cells harbored a unique methylome, with 8862 differentially methylated regions compared to LIC and 9444 compared to LDC, most of which were hypermethylated. Consistent with global hypermethylation, transcript levels of TET1 and TET3 methylcytosine dioxygenases were lower in LSC. Integrative analyses revealed an inverse relationship between methylation and gene expression changes during LSC differentiation. In LSC, hypermethylation suppressed the genes important for myometrium- and LM-associated functions, including muscle contraction and hormone action, to maintain stemness. The hypomethylating drug, 5′-Aza, stimulated LSC differentiation, depleting the stem cell population and inhibiting tumor initiation. Our data suggest that DNA methylation maintains the pool of LSC, which is critical for the regeneration of LM tumors.",

keywords = "DNA methylation, Stem cell differentiation, Uterine leiomyoma",

author = "Shimeng Liu and Ping Yin and Jingting Xu and Dotts, {Ariel J.} and Kujawa, {Stacy A.} and Coon, {John S.V.} and Hong Zhao and Ali Shilatifard and Yang Dai and Bulun, {Serdar E.}",

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AU - Liu, Shimeng

AU - Yin, Ping

AU - Xu, Jingting

AU - Dotts, Ariel J.

AU - Kujawa, Stacy A.

AU - Coon, John S.V.

AU - Zhao, Hong

AU - Shilatifard, Ali

AU - Dai, Yang

AU - Bulun, Serdar E.

N1 - Publisher Copyright: © Endocrine Society 2020. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Uterine leiomyoma (LM) is the most common tumor in women and can cause severe morbidity. Leiomyoma growth requires the maintenance and proliferation of a stem cell population. Dysregulated deoxyribonucleic acid (DNA) methylation has been reported in LM, but its role in LM stem cell regulation remains unclear. Here, we fluorescence-activated cell sorting (FACS)-sorted cells from human LM tissues into 3 populations: LM stem cell-like cells (LSC, 5%), LM intermediate cells (LIC, 7%), and differentiated LM cells (LDC, 88%), and we analyzed the transcriptome and epigenetic landscape of LM cells at different differentiation stages. Leiomyoma stem cell-like cells harbored a unique methylome, with 8862 differentially methylated regions compared to LIC and 9444 compared to LDC, most of which were hypermethylated. Consistent with global hypermethylation, transcript levels of TET1 and TET3 methylcytosine dioxygenases were lower in LSC. Integrative analyses revealed an inverse relationship between methylation and gene expression changes during LSC differentiation. In LSC, hypermethylation suppressed the genes important for myometrium- and LM-associated functions, including muscle contraction and hormone action, to maintain stemness. The hypomethylating drug, 5′-Aza, stimulated LSC differentiation, depleting the stem cell population and inhibiting tumor initiation. Our data suggest that DNA methylation maintains the pool of LSC, which is critical for the regeneration of LM tumors.

AB - Uterine leiomyoma (LM) is the most common tumor in women and can cause severe morbidity. Leiomyoma growth requires the maintenance and proliferation of a stem cell population. Dysregulated deoxyribonucleic acid (DNA) methylation has been reported in LM, but its role in LM stem cell regulation remains unclear. Here, we fluorescence-activated cell sorting (FACS)-sorted cells from human LM tissues into 3 populations: LM stem cell-like cells (LSC, 5%), LM intermediate cells (LIC, 7%), and differentiated LM cells (LDC, 88%), and we analyzed the transcriptome and epigenetic landscape of LM cells at different differentiation stages. Leiomyoma stem cell-like cells harbored a unique methylome, with 8862 differentially methylated regions compared to LIC and 9444 compared to LDC, most of which were hypermethylated. Consistent with global hypermethylation, transcript levels of TET1 and TET3 methylcytosine dioxygenases were lower in LSC. Integrative analyses revealed an inverse relationship between methylation and gene expression changes during LSC differentiation. In LSC, hypermethylation suppressed the genes important for myometrium- and LM-associated functions, including muscle contraction and hormone action, to maintain stemness. The hypomethylating drug, 5′-Aza, stimulated LSC differentiation, depleting the stem cell population and inhibiting tumor initiation. Our data suggest that DNA methylation maintains the pool of LSC, which is critical for the regeneration of LM tumors.

KW - DNA methylation

KW - Stem cell differentiation

KW - Uterine leiomyoma

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Targeting DNA methylation depletes uterine leiomyoma stem cell-enriched population by stimulatingtheir differentiation

Abstract

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Keywords

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