We all assume that water, good old H2O, has nothing to hide; however, dihydrogen monoxide has more than a few skeletons in its closet. For example, water is the leading cause of drowning while 100 percent of all people exposed to water will eventually die! It is easy to chalk up the second of these somewhat dubious claims as correlation rather than causation, but some similar claims are more difficult to reason out.
One such conundrum lies in understanding the epigenetics of aging: even though we can predict chronological and biological age through analysis of DNA methylation alterations (check our new eBook here!), we still do not fully understand if changes to DNA methylation levels actually cause aging or if they are merely “bystanders” of the processes underlying aging.
Now, a new study led by Christof Niehrs (Institute of Molecular Biology, Mainz, Germany) provides evidence of a “causal nexus” between DNA demethylation and aging in a study assessing the consequences of knocking-out two adapter proteins (GADD45α and ING1) involved in TET (ten-eleven translocation)-mediated DNA demethylation.
Fascinatingly, while studying this system, Schäfer and colleagues discovered a causative role for DNA hypermethylation of CEBP (CCAAT/enhancer-binding protein)-dependent adipogenic super-enhancers in the early onset of aging in mice. Of note, CEBP factors bind promoters and recruit co-activators to modulate the chromatin environment and/or recruit basal transcription factors and play central roles in metabolism and nutrient sensing.
Here are the details of this first-of-its-kind study:
- Loss of GADD45a/ING1 in model mice led to the premature appearance of some of the characteristic signs of aging
- The induced aging characteristics include reduced lifespan, excess curvature of the spine, weight loss (and deregulated adipose maintenance), female infertility, bone marrow fattening, and skin senescence
- Interestingly, the authors noted that phenotype of GADD45A/ING1 loss displays many similarities to the known early aging phenotype of CEBP mutations
- Similarities include deregulated adipose maintenance
- Analysis of normal and GADD45A/ING1 double-knockout mouse embryonic fibroblasts by whole-genome bisulfite sequencing (WGBS-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) established that GADD45α targets and promotes DNA demethylation at specific CEBP-dependent adipogenic super-enhancers
- DNA demethylation normally permits efficient CEBP recruitment by long-range chromatin looping through cooperation with ING1-bound at distant promoters
- Therefore, the promotion of DNA hypermethylation of adipogenic super-enhancer elements caused by GADD45a/ING1 loss can induce the early signs of aging
Overall, the authors posit that this exciting new study supports the hypothesis that DNA methylation alterations play causative roles in the aging process by uncovering a causal nexus between DNA demethylation and aging.
For more on this exciting new advance, see Genes and Development, June 2018.