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Age-Like Methylation Changes of HSCs in GADD45B Knockout Mice Define Methylation Sites Associated With Loss of
Wakako Kuribayashi1, Mayuri Tanaka-Yano1, Bongsoo Park1
1Epigenetics and Stem Cell Aging Unit, TGB, National Institute on Aging, NIH, Baltimore, Maryland, USA.
Insights
Growth Arrest and DNA Damage-inducible protein beta (Gadd45b) influences DNA methylation in hematopoietic stem cells (HSCs). Gadd45b knockout HSCs show altered methylation but retain functional potential, suggesting these sites do not drive age-related HSC dysfunction.
Area of Science:
- Hematology
- Epigenetics
- Stem Cell Biology
Background:
- Hematopoietic stem cells (HSCs) maintain blood cell production but decline with age.
- DNA methylation changes in aged HSCs contribute to dysfunction.
- Growth Arrest and DNA Damage-inducible proteins (Gadd45a, Gadd45b, Gadd45g) are involved in HSC activation, with Gadd45b potentially inducing DNA demethylation.
Purpose of the Study:
- To investigate the role of Gadd45b in DNA methylation and age-related HSC changes.
- To determine if Gadd45b-mediated methylation alterations impact HSC function.
Main Methods:
- Whole-genome bisulfite sequencing (WGBS) on HSCs from GADD45B knockout and aged wild-type mice.
- Peripheral blood and bone marrow analysis.
- Competitive transplantation and single-cell culture assays.
Main Results:
- Young GADD45B knockout HSCs exhibit increased DNA methylation compared to aged wild-type HSCs, with distinct methylation patterns.
- These methylation alterations in knockout HSCs did not lead to a significant loss of functional potential.
- Transcriptional changes associated with aging were not reflected in the methylation alterations observed.
Conclusions:
- Altered DNA methylation sites in GADD45B knockout HSCs do not compromise HSC potential.
- Identified methylation sites associated with HSC function can be prioritized for targeting age-related HSC decline.
- Generated a searchable HSC DNA methylation database for future research.
Abstract:
Hematopoietic stem cells (HSCs) self-renew and differentiate into all blood cells maintaining the hematopoietic system. Age-related HSC dysfunction impacts all of hematopoiesis, with DNA methylation alterations in aged HSCs contributing to altered function. Growth Arrest and DNA Damage-inducible proteins (Gadd45a, Gadd45b, and Gadd45g) are expressed in HSC activation, and Gadd45b has been reported to induce DNA demethylation. Thus, we explored the relationship between Gadd45b, DNA methylation and age-related HSC changes. WGBS on HSCs from GADD45B knockout mice demonstrated young knockout HSCs have increased DNA methylation, with both unique and overlapping methylation changes compared to aged wild-type HSCs without reflecting aging transcriptional changes. Peripheral blood and bone marrow analysis, competitive transplants, and single-cell culture analyses showed no significant loss of functional potential in the aberrantly methylated GADD45B knockout HSCs. We concluded these altered methylation sites don't alter HSC potential. We generated a searchable HSC DNA methylation database incorporating available datasets and present a truncated list of methylation sites associated with changes in HSC function for prioritization to target for resetting the age-associated loss of HSC potential.
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