Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal

Deqiang Sun; Min Luo; Mira Jeong; Benjamin Rodriguez; Zheng Xia; Rebecca Hannah; Hui Wang; Thuc Le; Kym F. Faull; Rui Chen; Hongcang Gu; Christoph Bock; Alexander Meissner; Berthold Göttgens; Gretchen J. Darlington; Wei Li; Margaret A. Goodell

doi:10.1016/j.stem.2014.03.002

Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal

Deqiang Sun, Min Luo, Mira Jeong, Benjamin Rodriguez, Zheng Xia, Rebecca Hannah, Hui Wang, Thuc Le, Kym F. Faull, Rui Chen, Hongcang Gu, Christoph Bock, Alexander Meissner, Berthold Göttgens, Gretchen J. Darlington, Wei Li, Margaret A. Goodell

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463 Scopus citations

Abstract

To investigate the cell-intrinsic aging mechanisms that erode the function of somatic stem cells during aging, we have conducted a comprehensive integrated genomic analysis of young and aged cells. We profiled the transcriptome, DNA methylome, and histone modifications of young and old murine hematopoietic stem cells (HSCs). Transcriptome analysis indicated reduced TGF-β signaling and perturbation of genes involved in HSC proliferation and differentiation. Aged HSCs exhibited broader H3K4me3 peaks across HSC identity and self-renewal genes and showed increased DNA methylation at transcription factor binding sites associated with differentiation-promoting genes combined with a reduction at genes associated with HSC maintenance. Altogether, these changes reinforce HSC self-renewal and diminish differentiation, paralleling phenotypic HSC aging behavior. Ribosomal biogenesis emerged as a particular target of aging with increased transcription of ribosomal protein and RNA genes and hypomethylation of rRNA genes. This data set will serve as a reference for future epigenomic analysis of stem cell aging.

Original language	English (US)
Pages (from-to)	673-688
Number of pages	16
Journal	Cell Stem Cell
Volume	14
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2014.03.002
State	Published - May 1 2014
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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Sun, D., Luo, M., Jeong, M., Rodriguez, B., Xia, Z., Hannah, R., Wang, H., Le, T., Faull, K. F., Chen, R., Gu, H., Bock, C., Meissner, A., Göttgens, B., Darlington, G. J., Li, W., & Goodell, M. A. (2014). Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell, 14(5), 673-688. https://doi.org/10.1016/j.stem.2014.03.002

Sun, D, Luo, M, Jeong, M, Rodriguez, B, Xia, Z, Hannah, R, Wang, H, Le, T, Faull, KF, Chen, R, Gu, H, Bock, C, Meissner, A, Göttgens, B, Darlington, GJ, Li, W & Goodell, MA 2014, 'Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal', Cell Stem Cell, vol. 14, no. 5, pp. 673-688. https://doi.org/10.1016/j.stem.2014.03.002

@article{ef578ed4c9ad408eaaa5a8deb86318be,

title = "Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal",

abstract = "To investigate the cell-intrinsic aging mechanisms that erode the function of somatic stem cells during aging, we have conducted a comprehensive integrated genomic analysis of young and aged cells. We profiled the transcriptome, DNA methylome, and histone modifications of young and old murine hematopoietic stem cells (HSCs). Transcriptome analysis indicated reduced TGF-β signaling and perturbation of genes involved in HSC proliferation and differentiation. Aged HSCs exhibited broader H3K4me3 peaks across HSC identity and self-renewal genes and showed increased DNA methylation at transcription factor binding sites associated with differentiation-promoting genes combined with a reduction at genes associated with HSC maintenance. Altogether, these changes reinforce HSC self-renewal and diminish differentiation, paralleling phenotypic HSC aging behavior. Ribosomal biogenesis emerged as a particular target of aging with increased transcription of ribosomal protein and RNA genes and hypomethylation of rRNA genes. This data set will serve as a reference for future epigenomic analysis of stem cell aging.",

author = "Deqiang Sun and Min Luo and Mira Jeong and Benjamin Rodriguez and Zheng Xia and Rebecca Hannah and Hui Wang and Thuc Le and Faull, {Kym F.} and Rui Chen and Hongcang Gu and Christoph Bock and Alexander Meissner and Berthold G{\"o}ttgens and Darlington, {Gretchen J.} and Wei Li and Goodell, {Margaret A.}",

note = "Funding Information: This work is dedicated to Estela Medrano. We thank Julio Hernandez for mouse management and Chris Threeton for flow cytometry. This work was supported by grants AG036562, AG288652, CA126752, DK092883, CA125123, DK084259, DK056338, AI07495, and AG000183 as well as the Ellison Medical Foundation, CPRIT grant RP110028, and the Samuel Waxman Cancer Research Foundation as well as HG007538, CPRIT RP110471, and DOD W81XWH-10-1-0501 to W.L. Support for T.L. came from T32 MH 19384-14, T32-HD007032, and the Eugene V. Cota-Robles Fellowship. ",

year = "2014",

month = may,

day = "1",

doi = "10.1016/j.stem.2014.03.002",

language = "English (US)",

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T1 - Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal

AU - Sun, Deqiang

AU - Luo, Min

AU - Jeong, Mira

AU - Rodriguez, Benjamin

AU - Xia, Zheng

AU - Hannah, Rebecca

AU - Wang, Hui

AU - Le, Thuc

AU - Faull, Kym F.

AU - Chen, Rui

AU - Gu, Hongcang

AU - Bock, Christoph

AU - Meissner, Alexander

AU - Göttgens, Berthold

AU - Darlington, Gretchen J.

AU - Li, Wei

AU - Goodell, Margaret A.

N1 - Funding Information: This work is dedicated to Estela Medrano. We thank Julio Hernandez for mouse management and Chris Threeton for flow cytometry. This work was supported by grants AG036562, AG288652, CA126752, DK092883, CA125123, DK084259, DK056338, AI07495, and AG000183 as well as the Ellison Medical Foundation, CPRIT grant RP110028, and the Samuel Waxman Cancer Research Foundation as well as HG007538, CPRIT RP110471, and DOD W81XWH-10-1-0501 to W.L. Support for T.L. came from T32 MH 19384-14, T32-HD007032, and the Eugene V. Cota-Robles Fellowship.

PY - 2014/5/1

Y1 - 2014/5/1

N2 - To investigate the cell-intrinsic aging mechanisms that erode the function of somatic stem cells during aging, we have conducted a comprehensive integrated genomic analysis of young and aged cells. We profiled the transcriptome, DNA methylome, and histone modifications of young and old murine hematopoietic stem cells (HSCs). Transcriptome analysis indicated reduced TGF-β signaling and perturbation of genes involved in HSC proliferation and differentiation. Aged HSCs exhibited broader H3K4me3 peaks across HSC identity and self-renewal genes and showed increased DNA methylation at transcription factor binding sites associated with differentiation-promoting genes combined with a reduction at genes associated with HSC maintenance. Altogether, these changes reinforce HSC self-renewal and diminish differentiation, paralleling phenotypic HSC aging behavior. Ribosomal biogenesis emerged as a particular target of aging with increased transcription of ribosomal protein and RNA genes and hypomethylation of rRNA genes. This data set will serve as a reference for future epigenomic analysis of stem cell aging.

AB - To investigate the cell-intrinsic aging mechanisms that erode the function of somatic stem cells during aging, we have conducted a comprehensive integrated genomic analysis of young and aged cells. We profiled the transcriptome, DNA methylome, and histone modifications of young and old murine hematopoietic stem cells (HSCs). Transcriptome analysis indicated reduced TGF-β signaling and perturbation of genes involved in HSC proliferation and differentiation. Aged HSCs exhibited broader H3K4me3 peaks across HSC identity and self-renewal genes and showed increased DNA methylation at transcription factor binding sites associated with differentiation-promoting genes combined with a reduction at genes associated with HSC maintenance. Altogether, these changes reinforce HSC self-renewal and diminish differentiation, paralleling phenotypic HSC aging behavior. Ribosomal biogenesis emerged as a particular target of aging with increased transcription of ribosomal protein and RNA genes and hypomethylation of rRNA genes. This data set will serve as a reference for future epigenomic analysis of stem cell aging.

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JO - Cell Stem Cell

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IS - 5

ER -

Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal

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