A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging
Open accessAbstract
Heterochromatin in aging stem cells: Analysis of human aging syndromes, such as Werner syndrome (WS), may lead to greater understanding of both premature and normal aging. Zhang et al. generated isogenic WS-specific human embryonic stem cell lines (see the Perspective by Brunauer and Kennedy). WS-mesenchymal stem cells displayed features characteristic of premature aging, including heterochromatin disorganization. WRN protein thus functions in the maintenance of heterochromatin, and heterochromatin alterations may represent a driving force of human aging. Science , this issue p. 1160 ; see also p. 1093
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Written from the paper’s full text.
TL;DR
A human Werner syndrome (WS) model was generated by knocking out WRN in embryonic stem cells and differentiating them to mesenchymal stem cells (MSCs), which recapitulated premature cellular aging and heterochromatin disorganization. The work links WRN to heterochromatin stability through SUV39H1/HP1α/LAP2β and suggests heterochromatin loss as a driver of human MSC aging.
Key findings
- WRN-null MSCs showed premature aging phenotypes, including loss of proliferative potential, increased SA-β-gal-positive cells, upregulated p16Ink4a and p21Waf1, SASP activation, and accelerated attrition after transplantation into NOD/SCID mice.
- WRN-deficient MSCs had global loss of H3K9me3; of 73 H3K9me3-enriched “mountains” in wild-type MSCs, 28 (38%) were lost, and 24 (86%) of impaired mountains resided in sub-telomeric or sub-centromeric regions. RNA-seq identified 1,047 differentially expressed RefSeq genes.
- WRN bound H3K9me3-enriched centromeric loci α-Satellite and Satellite 2 and co-immunoprecipitated with SUV39H1, HP1α, and LAP2β; WRN depletion increased centromeric γ-H2AX and loss of H3K9me3 from these loci.
- Knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulated accelerated senescence, and MSCs from six old individuals (58–72 years) showed decreased WRN, H3K9me3, HP1α, SUV39H1, and LAP2β compared with six young individuals (7–26 years).
Methods
- Isogenic WRN-null human ESC lines were generated by knocking out exons 15 and 16 of WRN using helper-dependent adenoviral vector-mediated homologous recombination, then differentiated into MSCs.
- WRN-deficient and wild-type MSCs were analyzed by serial passaging, senescence assays, transplantation into NOD/SCID mice, copy number variation deep sequencing, immunostaining/electron microscopy, histone and DNA modification assays, ChIP-qPCR, co-immunoprecipitation, and RNA-seq.
- Primary dental pulp MSCs from six young (7–26 years) and six old (58–72 years) individuals were compared for heterochromatin marks.
Limitations
- The paper states that more extensive studies are needed to examine the role of heterochromatin disorganization during physiological aging.
- The model uses an isogenic ESC knockout rather than patient-derived iPSCs because WS patient fibroblast lines showed severe karyotypic abnormalities and secondary DNA mutations associated with advanced WS pathology.
- Evident from the text: the human primary MSC comparison is small (six per age group) and cross-sectional, and the causal role of heterochromatin disorganization in human aging is not established beyond cellular/MSC phenotypes and mouse transplantation; SUV39H2 and/or other factors may compensate for SUV39H1 deficiency in ESCs.
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Claims the paper makes
0 of 3 cited sources checked · 0 supported · 0 flagged
- Findingown data
28 (38%) of H3K9me3 mountains were lost in MSCs-WRN−/−.
“28 (38%) of these H3K9me3 mountains were lost in MSCs-WRN−/−”
Quote in the paperSubstantial claim - Findingown data
MSCs-SUV39H1H324K recapitulate premature aging phenotypes observed in WRN-deficient MSCs.
“MSCs-SUV39H1H324K recapitulated premature aging phenotypes observed in WRN deficient MSCs”
Quote in the paperSubstantial claim - Findingown data
Depletion of WRN results in loss of H3K9me3 from α-Sat and Sat2 loci.
“Depletion of WRN resulted in an increase in centromeric γ-H2AX signal and a loss of H3K9me3 from α-Sat and Sat2 loci”
Quote in the paperSubstantial claim - Findingown data
WRN-null ESC-derived MSCs show changes in heterochromatin architecture.
“changes in heterochromatin architecture”
Quote in the paperSubstantial claim - Findingown data
WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β.
“We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β.”
Quote in the paperSubstantial claim
- Findingown data
Differentiation of WRN-null ESCs to MSCs recapitulates features of premature cellular aging.
“Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging”
Quote in the paperSubstantial claim - Findingown data
WRN-null ESC-derived MSCs show a global loss of H3K9me3.
“a global loss of H3K9me3”
Quote in the paperSubstantial claim - Findingown data
Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence resembling WRN-deficient MSCs.
“Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs.”
Quote in the paperSubstantial claim - Findingown data
WRN-deficient MSCs show significant downregulation of the constitutive heterochromatin mark H3K9me3.
“revealed significant downregulation of the constitutive heterochromatin mark H3K9me3 in MSC-WRN−/−”
Quote in the paperSubstantial claim - Findingown data
Homozygous WRN null ESC lines were successfully generated.
“we successfully generated homozygous WRN null ESC lines (ESCs-WRN−/−)”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingown data
WRN deficiency in MSCs results in elevated DNA damage response.
“WRN deficiency in MSCs resulted in elevated DNA damage response (DDR)”
Quote in the paperSubstantial claim - Interpretationown data
Active heterochromatin destabilization promotes premature aging in MSCs.
“These results indicate that active heterochromatin destabilization promotes premature aging in MSCs.”
Quote in the paperSubstantial claim - Premisecitation
Werner syndrome is a premature aging disorder caused by WRN protein deficiency.
“Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Kudlow BA Kennedy BK Monnat RJ Jr Nat Rev Mol Cell Biol 8 394 404 2007 17450177 source
Not checked in the free run.
- Interpretationown data
WRN maintains heterochromatin stability.
“Our observations uncover a role for WRN in maintaining heterochromatin stability”
Quote in the paperSubstantial claim - Interpretationown data
Specific heterochromatin changes may underlie both pathological and physiological mesenchymal stem cell aging.
“Therefore, specific heterochromatin changes may underlie both pathological as well as physiological mesenchymal stem cell aging.”
Quote in the paperSubstantial claim- Rests on an assumption: Primary dental pulp MSCs from old individuals are representative of physiological human stem cell aging.
- Interpretationown data
Loss of WRN promotes premature senescence in MSCs.
“These results demonstrated that the loss of WRN promotes premature senescence in MSCs.”
Quote in the paperSubstantial claim - Interpretationown data
Heterochromatin disorganization is a potential determinant of human aging.
“highlight heterochromatin disorganization as a potential determinant of human aging.”
Quote in the paperSubstantial claim
- May combine two claims. 2
May combine two claims.
Findingown dataKnockdown of SUV39H1 or HP1α in wild-type MSCs reduces overall H3K9me3 and induces cellular senescence.
“Knockdown of SUV39H1 or HP1α in wild-type MSCs led to a significant reduction of overall H3K9me3 and induction of cellular senescence”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDecrease in WRN and heterochromatin marks are detected in MSCs from older individuals.
“Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Primary dental pulp MSCs from old individuals are representative of physiological human stem cell aging.
“we compared the levels of heterochromatin marks in primary dental pulp MSCs derived from six young (7–26 year old) and six old (58–72 year old) individuals”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Changes in chromatin state have been strongly implicated in ageing by progeroid syndromes, which disrupt the nuclear lamina and its associated regulation of heterochromatin structure.
“Nonetheless, changes in chromatin state have been strongly implicated in ageing by progeroid syndromes, which disrupt the nuclear lamina and its associated regulation of heterochromatin structure142,143.”
From Measuring biological age using omics data (2022) · cites this paper as [143]
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Shiels, P. G., McGuinness, D., Eriksson, M., Kooman, J. P., & Stenvinkel, P. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.78 · Cited by 114 · see citing works
Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging
Liu, Z., Ji, Q., Ren, J., Yan, P., Wu, Z., Wang, S., Sun, L., Wang, Z., Li, J., Sun, G., et al. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.05.004 · Cited by 109 · see citing works
Self-citationThe Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription
Tang, W., Robles, A. I., Beyer, R. P., Gray, L. T., Nguyen, G. H., Oshima, J., Maizels, N., Harris, C. C., & Monnat, R. J. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw079 · Cited by 109 · see citing works
Zhang, Y., Amaral, M. L., Zhu, C., Grieco, S. F., Hou, X., Lin, L., Buchanan, J., Tong, L., Preissl, S., Xu, X., et al. (2022) · Cell Research · doi:10.1038/s41422-022-00719-6 · Cited by 89 · see citing works
Self-citationNaked Mole Rat Cells Have a Stable Epigenome that Resists iPSC Reprogramming
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DNA double strand break repair, aging and the chromatin connection
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ATF3 drives senescence by reconstructing accessible chromatin profiles
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“For examples, H3K9me3 is reduced in Werner syndrome model cells (W. Zhang et al., 2015), decrease of H4K16ac is observed in Zmpste-24-null fibroblasts(Krishnan et al., 2011), loss of H4K20me3 promotes senescence and aging (Lyu et al., 2018).”
BackgroundGenomic instability and DNA replication defects in progeroid syndromes
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DNA damage in aging, the stem cell perspective
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Genome engineering of stem cell organoids for disease modeling
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The functional impact of nuclear reorganization in cellular senescence
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Dysregulation of Mesenchymal Stromal Cell Antioxidant Responses in Progressive Multiple Sclerosis
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Extreme disruption of heterochromatin is required for accelerated hematopoietic aging
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The link between Mitochondria and Sarcopenia
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Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals
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Self-citationRECQ DNA Helicases and Osteosarcoma
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- Authors
- Zhang, W., Li, J., Suzuki, K., Qu, J., Wang, P., Zhou, J., Liu, X., Ren, R., Xu, X., Ocampo, A., Yuan, T., Yang, J., Li, Y., Shi, L., Guan, D., Pan, H., Duan, S., Ding, Z., Li, M., Yi, F., Bai, R., Wang, Y., Chen, C., Yang, F., Li, X., Wang, Z., Aizawa, E., Goebl, A., Soligalla, R. D., Reddy, P., Esteban, C. R., Tang, F., Liu, G.-H., & Belmonte, J. C. I.
- Affiliations
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Salk Institute for Biological Studies (US)
- PLA 306 Hospital (CN)
- Stanford Medicine (US)
- Shenzhen University (CN)
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
- Corresponding author
- Zhang, Weiqi
- Li, Jingyi
- Suzuki, Keiichiro
- Qu, Jing
- Tang, Fuchou
- Liu, Guang-Hui
- ORCID
- Zhang, Weiqi
- Li, Jingyi
- Suzuki, Keiichiro
- Qu, Jing
- Wang, Ping
- Zhou, Junzhi
- Liu, Xiaomeng
- Ren, Ruotong
- Xu, Xiuling
- Ocampo, Alejandro
- Yuan, Tingting
- Yang, Jiping
- Li, Ying
- Shi, Liang
- Pan, Huize
- Duan, Shunlei
- Ding, Zhichao
- Li, Mo
- Yi, Fei
- Bai, Ruijun
- Wang, Yayu
- Chen, Chang
- Yang, Fuquan
- Li, Xiaoyu
- Wang, Zimei
- Aizawa, Emi
- Goebl, April
- Reddy, Pradeep
- Tang, Fuchou
- Liu, Guang-Hui
- Venue
- Science
- Published
- 2015-06-05
- Volume
- 348
- Issue
- 6239
- Pages
- 1160-1163
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4494668
- OpenAlex
- W2078291208
- Semantic Scholar
- fe6fc7c4760ab07bf348ec335672fc5830ced807
- Cited by
- 551
- References
- 50
- Citations by year
- 2026: 39 · 2025: 40 · 2024: 51 · 2023: 43 · 2022: 44 · 2021: 60 · 2020: 53 · 2019: 57 · 2018: 51 · 2017: 47 · 2016: 50 · 2015: 15 · 2014: 1
- FWCI
- 40.04
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-03-20)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Natural Science Foundation of China (81330008)
- NSFC (31222039, 31201111, 81371342, 81300261, 81300677, 81271266, 81471414, 81422017, 81401159, 31322037, 81471407)
- China Postdoctoral Science Foundation (2013M530751)
- Beijing Natural Science Foundation (7141005, 5142016)
- National Basic Research Program of China (2015CB964800, 2014CB910500, 2014CB964600, 2012CB966704)
- Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01020312)
- National High Technology Research and Development Program of China (2015AA020307)
- Key Research Program of the Chinese Academy of Sciences (KJZDEW-TZ-L05)
- Thousand Young Talents program of China (SIMM1302KF-17)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Werner syndrome, WRN protein, premature aging, human embryonic stem cells, mesenchymal stem cells, heterochromatin, H3K9me3, SUV39H1, HP1α, cellular senescence, human aging
- MeSH terms
- Werner Syndrome Helicase, Chromobox Protein Homolog 5, Aging, Animals, Cell Differentiation, Centromere, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Exodeoxyribonucleases, Heterochromatin, Humans, Membrane Proteins, Methyltransferases, Models, Biological, Repressor Proteins, Werner Syndrome, Cellular Senescence, Epigenesis, Genetic, Mice, RecQ Helicases, Gene Knockout Techniques, HEK293 Cells, Mesenchymal Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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