Type 2 diabetes (T2D) is a multifactorial disease affecting over 450 million people in Europe alone, amounting to the burden of life-threatening diseases and worsening quality of life. Skeletal muscle is affected early in T2D and contributes to the fast decline of whole-body glucose homeostasis, which is called insulin resistance. Interestingly, even when isolated from the body and cultured in a laboratory in non-diabetogenic conditions, the skeletal muscle cells do not lose the characteristics of the donor, i.e., the cells remain insulin resistant, indicating the existence of a cell-autonomous mechanism that retains the metabolic memory across generations of cells. Nonetheless, such a mechanism remains elusive. Accumulating evidence suggests a potential role of histone post-translational modifications as essential vectors of inheritable information, but it is still a matter of intense debate. In this project, to address this question and understand the pathology of T2D, we will trace a comprehensive genome-wide map of histone post-translational modifications induced by T2D in human primary skeletal muscle cells and investigate whether these histone marks can store and transmit information about the metabolic phenotype from the donor to the next generation of cells. Targeted studies using pharmacological and genetic interventions will then address the role of histone modifying enzymes in metabolic memory transmission. The outcomes could lead to a novel understanding of a broader system of cellular memory storage and transmission. By characterizing the disturbances caused by diabetes in the epigenome using state-of-the-art techniques and multidisciplinary approaches, we could pave the way for innovative clinical interventions addressing a critical global health challenge.