MACF1 promotes osteoblast differentiation by sequestering repressors in cytoplasm

Cell Death Differ. 2021 Jul;28(7):2160-2178. doi: 10.1038/s41418-021-00744-9. Epub 2021 Mar 4.


Osteoblast differentiation leading to bone formation requires a coordinated transcriptional program. Osteoblastic cells with low level of microtubule actin crosslinking factor 1 (MACF1) show reduced osteoblast differentiation ability, however, the comprehensive mechanism of MACF1's action remains unexplored. In the current study, we found that MACF1 knockdown suppressed osteoblast differentiation by altering the transcriptome dynamics. We further identified two MACF1-interacted proteins, cyclin-dependent kinase 12 (CDK12) and MYST/Esa1-associated factor 6 (MEAF6), and two MACF1-interacted transcription factors (TFs), transcription factor 12 (TCF12) and E2F transcription factor 6 (E2F6), which repress osteoblast differentiation by altering the expression of osteogenic TFs and genes. Moreover, we found that MACF1 regulated cytoplasmic-nuclear localization of itself, TCF12 and E2F6 in a concentration-dependent manner. MACF1 oppositely regulates the expression of TCF12 and transcription factor 7 (TCF7), two TFs that drive osteoblast differentiation to opposite directions. This study reveals that MACF1, a cytoskeletal protein, acts as a sponge for repressors of osteoblast differentiation to promote osteoblast differentiation and contributes to a novel mechanistic insight of osteoblast differentiation and transcription dynamics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation / genetics*
  • Cell Line
  • Cytoplasm / metabolism*
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Mice
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Osteoblasts / metabolism
  • Osteogenesis / genetics*
  • Signal Transduction


  • Basic Helix-Loop-Helix Transcription Factors
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Macf1 protein, mouse
  • Microfilament Proteins
  • Tcf12 protein, mouse