Developmentally Established Chromatin Accessibility and Locus Reuse - A Framework for Locus-Level Pleiotropy

Chromatin accessibility is dynamically regulated during development through interactions between physiological signalling pathways, sequence-specific transcription factors and chromatin-modifying machinery (Heinz et al., 2015; Voss & Hager, 2014; Klemm et al., 2019). These processes establish accessibility states that contribute to transcriptional potential within specific developmental contexts. Here, I propose that accessibility established during the primary developmental utilisation of a genomic locus can persist as a bias in later responsiveness. Primary developmental utilisation refers to locus engagement during the developmental establishment of cellular or tissue identity, rather than the first-ever transcriptional use of a locus. If the same locus is subsequently reused across distinct cellular programmes, a shared accessibility bias could influence multiple downstream processes without requiring those processes to be directly coupled. Developmental and single-cell epigenomic studies demonstrate extensive accessibility remodelling during lineage specification, while persistent or primed accessibility states have been observed following earlier regulatory encounters and at developmental loci in adult human cells (Corces et al., 2016; Cusanovich et al., 2018a; Tu et al., 2017; Kabbe et al., 2026). Large-scale regulatory studies likewise demonstrate reuse of regulatory architecture across cell types and phenotypes (Nasser et al., 2021; Qi et al., 2024). These observations establish the plausibility of the component relationships but do not demonstrate their proposed coupling. The distinctive claim of this framework is that developmentally conditioned accessibility at a reused locus may provide a mechanistic route to locus-level pleiotropy. The model predicts cross-context covariance in locus responsiveness, developmental timing effects, context-specific downstream consequences, and a decisive test in which perturbation of accessibility during primary developmental utilisation alters later responsiveness of the same locus across more than one subsequent context.