Description
The stability of nuclear lamina and histone modifications is critical in the aging process and cellular senescence. Our study investigates the response of naked mole rat (NMR) cells to aging conditions induced by doxycycline (dox)-regulated progerin-GFP expression, comparing it to human dermal fibroblasts (HDF). Employing a high-throughput immunofluorescence assay, we have investigated a wide range of markers within thousands of single cells to monitor epigenetic and cellular changes in both species.
Progerin expression resulted in epigenetic changes associated with aging in both species, including the reduction of total histone H3 levels, decreased H3K27ac/-me3 and increased H4K20me3 levels. These changes indicate that the model effectively replicates some aspects of the aging.
However, we also observed stark differences in response to progerin in NMR versus HDF fibroblasts which we believe may uncover certain protective mechanisms in NMR against cellular age-inducing stresses. For example, progerin expression is associated with heterochromatin loss which we could replicate in our HDF system via a reduction of Lamin B and H3K9me3. In contrast, both Lamin B and H3K9me3 showed remarkable stability. This result suggests that NMRs have an optimised mechanism for ensuring maintenance of genome organisation under damaging conditions which we are now investigating.
We also observed comparable responses in other aging markers including p16Ink4a, p21, and gamma-H2AX. These markers of cell-cycle arrest and DNA damage response followed the expected aging phenotype. Additionally, the expression of p53 was increased in NMR cells but not in HDFs after progerin induction.
Altogether, the divergent response of NMRs fibroblasts compared to HDFs sheds insights into various protective mechanisms employed by the NMR cell in the face of aging-associated cellular damages. These in turn can be further explored and leveraged for the development of novel anti-aging therapeutic strategies.
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