MApping the Methylation of repetitive elements to track the Exposome effects on health: the city of Legnano as a LIving lab

Introduction

The concept of “exposome” encompasses all human disease determinants encountered during the life course. The exposome induces epigenetic modifications (e.g., DNA methylation). Several studies have investigated how repetitive elements (REs) can be switched on in response to environmental stimuli, but have started from the assumption that altered RE methylation is always detrimental to the health of the affected individual.

Hypothesis

MAMELI proposes an alternative hypothesis that some REs are plastic entities that respond physiologically to the environment; consequently, the ability of DNA to adapt to environmental triggers can be monitored.

Study Design

To test this hypothesis, the MAMELI project will enroll 6200 subjects in the city of Legnano (Italy). The study will be conducted in three levels:

1. Discovery Level:

   • This first-level will apply third-generation sequencing methylation assessment on 200 subjects at two-time points: T0 (baseline) and T1 (6 months after T0).
   • The discovery level will allow the definition of a pool of REs (“differential REs”) whose methylation can change without impacting genome stability.

2. Tuning Level:

   • This second level will be conducted on 2700 subjects (200 subjects from the discovery level + 2500 additional subjects).
   • It will allow the development of an algorithm (“MAMELI algorithm”) to predict the relationship between exposome and RE methylation status (“RE methylation signature”).

3. Validation Level:

   • In the third level, the MAMELI algorithm will be applied to the second set of the study cohort (n=3500) to calculate the difference between the measured RE methylation signature and the values predicted by the algorithm.
   • Additionally, to test the reversibility of RE methylation following lifestyle modifications and its preventive potential, an intervention study will be designed and embedded in the cohort.

Conclusion

MAMELI would represent a breakthrough in the understanding of individual susceptibility to environmental pressures, enabling the development of preventive strategies to avoid disease.