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A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes.

Publication ,  Journal Article
Baksh, SS; Pratt, RE; Gomez, J; Dzau, VJ; Hodgkinson, CP
Published in: J Biol Chem
June 2022

miRNA-based cellular fate reprogramming offers an opportunity to investigate the mechanisms of long-term gene silencing. To further understand how genes are silenced in a tissue-specific manner, we leveraged our miRNA-based method of reprogramming fibroblasts into cardiomyocytes. Through screening approaches, we identified three proteins that were downregulated during reprogramming of fibroblasts into cardiomyocytes: heterochromatin protein Cbx1, transcriptional activator protein PurB, and transcription factor Sp3. We show that knockdown of Cbx1, PurB, and Sp3 was sufficient to induce cardiomyocyte gene expression in fibroblasts. Similarly, gene editing to ablate Cbx1, PurB, and Sp3 expression induced fibroblasts to convert into cardiomyocytes in vivo. Furthermore, high-throughput DNA sequencing and coimmunoprecipitation experiments indicated that Cbx1, PurB, and Sp3 also bound together as a complex and were necessary to localize nucleosomes to cardiomyocyte genes on the chromosome. Finally, we found that the expression of these genes led to nucleosome modification via H3K27me3 (trimethylated histone-H3 lysine-27) deposition through an interaction with the polycomb repressive PRC2 complex. In summary, we conclude that Cbx1, PurB, and Sp3 control cell fate by actively repressing lineage-specific genes.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

June 2022

Volume

298

Issue

6

Start / End Page

102053

Location

United States

Related Subject Headings

  • Sp3 Transcription Factor
  • Polycomb-Group Proteins
  • Myocytes, Cardiac
  • MicroRNAs
  • Mice
  • Humans
  • Heterochromatin
  • Gene Silencing
  • DNA-Binding Proteins
  • Chromobox Protein Homolog 5
 

Citation

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Baksh, S. S., Pratt, R. E., Gomez, J., Dzau, V. J., & Hodgkinson, C. P. (2022). A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes. J Biol Chem, 298(6), 102053. https://doi.org/10.1016/j.jbc.2022.102053
Baksh, Syeda Samara, Richard E. Pratt, José Gomez, Victor J. Dzau, and Conrad P. Hodgkinson. “A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes.J Biol Chem 298, no. 6 (June 2022): 102053. https://doi.org/10.1016/j.jbc.2022.102053.
Baksh SS, Pratt RE, Gomez J, Dzau VJ, Hodgkinson CP. A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes. J Biol Chem. 2022 Jun;298(6):102053.
Baksh, Syeda Samara, et al. “A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes.J Biol Chem, vol. 298, no. 6, June 2022, p. 102053. Pubmed, doi:10.1016/j.jbc.2022.102053.
Baksh SS, Pratt RE, Gomez J, Dzau VJ, Hodgkinson CP. A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes. J Biol Chem. 2022 Jun;298(6):102053.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

June 2022

Volume

298

Issue

6

Start / End Page

102053

Location

United States

Related Subject Headings

  • Sp3 Transcription Factor
  • Polycomb-Group Proteins
  • Myocytes, Cardiac
  • MicroRNAs
  • Mice
  • Humans
  • Heterochromatin
  • Gene Silencing
  • DNA-Binding Proteins
  • Chromobox Protein Homolog 5