Redundancy, noise, and plasticity: repetitive DNA as an epigenetic intelligence backbone of inflammatory regulation

Repetitive DNA elements such as LINE1 have been proposed to support a redundant distributed, adaptive layer of gene regulation, contributing to "Epigenetic Intelligence" (EI). However, empirical evidence for their role in modulating inflammatory responses to environmental exposures remains limited.

We investigated whether the association of PM with an aerodynamic diameter ≤10 µm (PM₁₀) with fibrinogen levels is modulated by LINE1 methylation (effect modification), acting as an epigenetic buffer of systemic inflammation in response to air pollution, looking at the EI hypothesis.

We analyzed data from the SPHERE cohort (n = 1630), a population-based study in Northern Italy. Daily residential exposure to PM₁₀ was estimated, and LINE1 methylation was assessed via pyrosequencing. Fibrinogen was used as a biomarker of systemic inflammation. Generalized Additive Models with tensor product interactions were used to evaluate the PM₁₀ × LINE1 interaction, adjusting for relevant confounders.

The interaction between PM₁₀ exposure and LINE1 methylation was statistically supported (EDF ≈ 4.45, P < 0.001), with the model explaining ∼33% of deviance (adj. R² = 0.39). Individuals in the lowest tertile of LINE1 methylation exhibited a stronger positive association between PM₁₀ and fibrinogen, whereas those in the highest tertile showed a blunted response, suggesting a buffering modification effect. Results were confirmed by MARS models.

Our findings were coherent with the concept of EI. LINE1 methylation modulates the inflammatory response to environmental stressors, possibly acting as an adaptive epigenetic filter that buffers weak or transient signals. This distributed regulatory capacity may be critical for immune homeostasis under the dynamic environmental challenge.