The Critical Role of Ets1 in Preserving Chromatin Architecture for Osteogenic Differentiation Priming
Osteoblast differentiation plays a central role in skeletal development and bone tissue maintenance, and is orchestrated by a tightly regulated series of molecular events. While changes in transcriptional activity are fundamental to this process, accumulating evidence suggests that broader epigenomic mechanisms including chromatin remodeling and spatial genome reorganization also contribute significantly to lineage specification. To date, research in this area has largely concentrated on defining the functions of major transcription factors such as Runx2 and Sp7, or profiling gene expression changes during differentiation. However, the regulatory landscape that precedes overt transcriptional activation, particularly at the level of three dimensional (3D) genome architecture, remains poorly defined. Although previous studies have highlighted the relevance of epigenetic modifications such as DNA methylation and histone acetylation in osteogenic differentiation, how these marks translate into coordinated structural transitions within the genome is still unclear. Recent findings have drawn attention to the possibility that certain enhancer regions may be epigenetically primed prior to external differentiation cues, enabling rapid transcriptional activation upon signal reception. In particular, enhancers regulated by ETS family transcription factors have emerged as critical nodes in the regulatory networks of multiple tissue types, though their functional relevance in bone-forming lineages remains to be fully explored. In the present study, we investigated early chromatin dynamics during osteoblast differentiation, with a focus on the relationship between changes in compartment identity and chromatin accessibility. By integrating transcriptomic, epigenomic, and chromatin conformation data, we identified Ets1 as a key factor that facilitates the activation of enhancers while concurrently driving compartment switching. Loss of Ets1 led to persistent repression of osteogenic genes, indicating its essential role in establishing a chromatin state permissive to differentiation. These findings support a model in which Ets1 serves as a chromatin priming factor, shaping the 3D genomic landscape to enable transcriptional programs necessary for osteoblast lineage commitment.