2. Academic Validation
  3. Myogenic enhancer snatching promotes adipogenic differentiation during epigenetic reprogramming mediated by lineage-specific transcription factors

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

  • Cell Mol Life Sci. 2025 Nov 19;82(1):412. doi: 10.1007/s00018-025-05901-8.
Mingyang Hu # 1,  Zhixiang Xu # 2,  Jiahao Sun # 2,  Linmi Li 2,  Pengxuan Liu 3,  Honghong Zhou 1,  Xiaolong Qi 1,  Weike Ren 3,  Yujia Liu 3,  Shuya Chen 3,  Renzhuo Kuang 2,  Daoyuan Wang 2,  Yaping Guo 2,  Ge Sun 4,  Shuhong Zhao 2 1,  Mengjin Zhu 5 6,  Li Li 7,  Yunxia Zhao 8 9
Affiliations

Affiliations

  • 1 Yazhouwan National Laboratory, Sanya, 572000, China.
  • 2 Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.
  • 3 College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China.
  • 4 Hainan Research Institute of Huazhong Agricultural University, Sanya, 572000, China.
  • 5 Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China. [email protected].
  • 6 Hainan Research Institute of Huazhong Agricultural University, Sanya, 572000, China. [email protected].
  • 7 College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China. [email protected].
  • 8 Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China. [email protected].
  • 9 Yazhouwan National Laboratory, Sanya, 572000, China. [email protected].
  • # Contributed equally.
PMID: 41258103 DOI: 10.1007/s00018-025-05901-8
Abstract

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.

Keywords

Cell fate; Chromatin interactions; Enhancer snatch; Trans-differentiation.

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