Myogenic enhancer snatching promotes adipogenic differentiation during epigenetic reprogramming mediated by lineage-specific transcription factors

The myoblast-to-adipocyte trans-differentiation model is crucial for studying the regulatory mechanisms underlying ectopic fat deposition and cell fate determination. However, the comprehensive dynamics of chromatin accessibility and interactions during this process remain largely unexplored. To address this, we performed an integrative analysis of bulk and single-cell multi-omics data (ATAC-seq, RNA-seq), and Hi-C data on an adipogenesis model in C2C12 myoblasts. Our findings revealed significant reprogramming of chromatin accessibility driven by adipogenic lineage-specific transcription factors (TFs), particularly Cebps and Stats, during trans-differentiation. Notably, 63.46% of the distal open chromatin regions with increased accessibility were shared between myogenesis and adipogenesis. Further joint analysis with Hi-C data suggests that these pre-established enhancers in myoblasts undergo a "regulatory redirection," shifting their influence from myogenic to adipogenic genes-a phenomenon we termed "enhancer snatch." This model was validated by knocking out a "snatched" enhancer (Enhancer-R/L), which was found to be a critical regulator of both Rbl1 and Lbp expression. Overall, our study uncovers a mechanism that pre-established enhancers in original cell lineage are predominantly utilized by lineage-specific TFs during chromatin reprogramming, thereby altering cell's differentiation trajectory.