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RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts.

Seyeon Bae1,2, Kibyeong Kim3,4, Keunsoo Kang5

  • 1Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, 10021, USA.

Cellular & Molecular Immunology
|December 13, 2022
PubMed
Summary

Researchers identified novel superenhancers (SEs) and enhancer RNAs (SE-eRNAs) that are specific to human osteoclasts. These SEs and SE-eRNAs are regulated by receptor activator of NF-κB ligand (RANKL) and are crucial for osteoclast differentiation.

Keywords:
OsteoclastsRheumatoid arthritisenhancer RNAssuper-enhancers

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Area of Science:

  • Epigenetics
  • Cell Biology
  • Immunology

Background:

  • Monocyte/macrophage lineage cells are plastic and differentiate into various cell types.
  • Osteoclasts, which resorb bone, differentiate from monocytes/macrophages upon stimulation by receptor activator of NF-κB ligand (RANKL).
  • The epigenetic mechanisms governing human osteoclast differentiation remain largely uncharacterized.

Purpose of the Study:

  • To identify epigenetic signatures, specifically superenhancers (SEs) and enhancer RNAs (SE-eRNAs), associated with human osteoclast differentiation.
  • To investigate the role of these SEs and SE-eRNAs in RANKL-induced osteoclastogenesis.
  • To explore the potential of these osteoclast-specific signatures as therapeutic targets.

Main Methods:

  • Integration of ChIP-seq, ATAC-seq, nuclear RNA-seq, and PRO-seq analyses.
  • Genome-wide identification of RANKL-responsive SEs and SE-eRNAs in human macrophages and osteoclasts.
  • Functional studies involving transcription factor depletion (BATF1/3) and SE-eRNA knockdown.
  • Analysis of SE-eRNA expression in patient samples (rheumatoid arthritis).

Main Results:

  • RANKL stimulation induced the formation of ~200 osteoclast-specific SEs and suppressed 148 SEs in macrophages.
  • RANKL-responsive SEs were enriched for BATF binding motifs; BATF depletion inhibited osteoclast differentiation.
  • Increased chromatin accessibility and SE-eRNA transcription (e.g., SE-eRNA:NFATc1) were observed in osteoclast SE regions.
  • Knockdown of SE-eRNAs, particularly SE-eRNA:NFATc1, impaired NFATc1 expression and osteoclast differentiation.
  • BET protein inhibition affected SE formation and SE-eRNA expression.
  • SE-eRNA:NFATc1 was highly expressed in synovial macrophages of rheumatoid arthritis patients.

Conclusions:

  • RANKL-inducible SEs and SE-eRNAs represent novel osteoclast-specific epigenetic signatures.
  • These findings highlight the critical role of SEs and SE-eRNAs in regulating osteoclast differentiation.
  • Osteoclast-specific SEs and SE-eRNAs offer potential targets for developing new therapeutic strategies for bone-resorbing diseases.