Epigenetic Inheritance: Maintaining and Fine-Tuning Origin-Specific Features Across Generations

Epigenetic inheritance refers to the transmission of gene regulatory information across generations without alterations in the underlying DNA sequence. Among its most striking manifestations is the faithful maintenance of parent-of-origin-specific expression and, in some cases, the nuanced refinement of origin-specific features from parent to offspring, wherein certain gene expressions are maintained preferentially from either the maternal or paternal allele, a phenomenon primarily governed by genomic imprinting. Central to this phenomenon are epigenetic modifications, including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodelers, which together preserve developmental programs, imprinting patterns, and stress responses across cellular and organismal generations. Additionally, environmental cues experienced by parents can reshape epigenomic landscapes and influence offspring phenotypes through transgenerational epigenetic inheritance. These heritable marks are not merely static carriers of information but are dynamically regulated to alter gene expression in response to developmental context and external demands. Understanding how epigenetic memory is selectively maintained, erased, or modified holds profound implications for human health, evolution, and the treatment of diseases caused by epigenomic dysregulation. In this review, we interpret the mechanisms underlying the maintenance of these origin-specific features in relation to the regulation and preservation of epigenetic marks during germline development and early embryogenesis. We discuss how some of these marks escape epigenetic reprogramming, enabling the faithful inheritance of regulatory states. Additionally, we highlight the role of epigenetic programming, imprinting disorders, and the effect of environmental factors in shaping transgenerational phenotypes. A deeper understanding of epigenetic inheritance provides valuable insights and holds promise for future therapeutic strategies aimed at correcting heritable epigenetic dysregulation.