Although protein-coding genes play a central role, they cannot fully explain stem cell differentiation and epigenetic control. These processes are largely directed by the non-coding genome, which comprises diverse regulatory elements and non-coding RNAs that orchestrate chromatin dynamics and establish epigenetic memory in both eukaryotic and microbial systems. Our goal is to systematically decipher how these elements control cell fate and maintain epigenetic states by focusing on their interplay with chromatin modifiers, histone variants , and microbial epigenetic systems (e.g., DNA methylation and non-coding RNAs in bacteria and archaea). The unique properties of non-coding RNAs (programmability, specificity, and the ability to recruit chromatin-regulatory complexes and modulate chromatin accessibility) make them ideal candidates for next-generation synthetic biology tools, including targeted epigenetic reprogramming in microbial and eukaryotic cells. By engineering such RNA-based devices, we aim to gain precise mechanistic insights into the function of the non-coding genome in diverse chromatin contexts. This will enable us to design sophisticated synthetic genomes for microbial synthetic biology, epigenetic engineering , and therapeutic interventions.