2026-10-14T11:40:09Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33994806 2026-09-25T11:39:52Z category_694 portal_316 item_type_3 month_year_09_2026

Table 1_From chromatin to proteostasis: multilevel gene regulation in Mendelian diseases.docx Himanshu Goel (509740) Gunjan Garg (17386294) Epigenetics (incl. Genome Methylation and Epigenomics) DNA methylation episignatures gene expression regulation Mendelian disease noncoding RNA proteostasis RNA splicing translational regulation <p>Pathogenic variation can alter gene output at multiple levels, from chromatin accessibility and enhancer-promoter communication to RNA processing, translation and protein turnover. The diagnostic challenge is not to catalogue these layers, but to determine which regulatory mechanism is plausible for a given variant, phenotype, tissue and developmental context. This targeted narrative review synthesises representative Mendelian mechanisms across five linked levels: chromatin, transcription, RNA processing and stability, translation, and post-translational proteostasis. Three cross-cutting principles recur. First, distinct molecular lesions may converge on the same functional bottleneck: altered dosage, timing, localisation or disrupted protein homeostasis. Second, regulatory effects are often cell-type-, isoform-, developmental-stage- and state-specific, so assay and tissue selection are integral to interpretation. Third, a negative result in an accessible surrogate such as blood does not exclude a disease-relevant effect in brain, muscle, liver or stimulated immune cells. From these principles, the review derives a mechanism-directed diagnostic framework that links variant class to orthogonal assays, including DNA methylation profiling, chromatin and reporter assays, RNA sequencing, ribosome-level methods and protein-based studies. The framework is offered as an integrative clinical synthesis rather than a new model of gene regulation, to support variant interpretation, functional-test selection and translational prioritisation in unsolved Mendelian disease.</p> 2026-09-25T11:39:52Z Dataset Dataset 10.3389/freae.2026.1944086.s001 https://figshare.com/articles/dataset/Table_1_From_chromatin_to_proteostasis_multilevel_gene_regulation_in_Mendelian_diseases_docx/33994806 CC BY 4.0