Skip to main content
NCBI home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1984 Feb 1;98(2):602–608. doi: 10.1083/jcb.98.2.602

Sodium butyrate induces histone hyperacetylation and differentiation of murine embryonal carcinoma cells

PMCID: PMC2113095  PMID: 6141173

Abstract

Cells from embryonal carcinoma (EC) lines 6050AJ and PCC4.aza 1R differentiate in response to treatment with sodium butyrate as well as retinoic acid (RA) or hexamethylenebisacetamide (HMBA). Murine 6050AJ EC cells exposed to sodium butyrate possess hyperacetylated forms of histones H4 and altered forms of histones H2a and H2b, whereas histones from cells treated with other inducers appear to be unaffected. These results might indicate that the mechanism by which sodium butyrate promotes differentiation of EC cells is different from the ways in which RA and HMBA act. Differentiation-defective PCC4(RA)-1 EC cells fail to respond to RA, presumably because they possess minimal amounts of active binding protein for RA (cRABP). Sodium butyrate treatment of these cells results in only a modest level of differentiation. On the other hand, exposure to sodium butyrate plus RA leads to extensive differentiation. As is the case with 6050AJ cells, PCC4(RA)-1 cells treated with sodium butyrate also contain hyperacetylated histones. Furthermore, these cells now possess high levels of cRABP. The latter observations suggest that sodium butyrate has the ability to reactivate a silent cRABP gene in PCC4(RA)-1 cells and thereby lead to extensive differentiation via the retinoid pathway when RA is added.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beers W. H., Strickland S., Reich E. Ovarian plasminogen activator: relationship to ovulation and hormonal regulation. Cell. 1975 Nov;6(3):387–394. doi: 10.1016/0092-8674(75)90188-9. [DOI] [PubMed] [Google Scholar]
  2. Boffa L. C., Vidali G., Mann R. S., Allfrey V. G. Suppression of histone deacetylation in vivo and in vitro by sodium butyrate. J Biol Chem. 1978 May 25;253(10):3364–3366. [PubMed] [Google Scholar]
  3. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  4. Candido E. P., Reeves R., Davie J. R. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell. 1978 May;14(1):105–113. doi: 10.1016/0092-8674(78)90305-7. [DOI] [PubMed] [Google Scholar]
  5. Compere S. J., Palmiter R. D. DNA methylation controls the inducibility of the mouse metallothionein-I gene lymphoid cells. Cell. 1981 Jul;25(1):233–240. doi: 10.1016/0092-8674(81)90248-8. [DOI] [PubMed] [Google Scholar]
  6. Franke W. W., Scheer U., Trendelenburg M., Zentgraf H., Spring H. Morphology of transcriptionally active chromatin. Cold Spring Harb Symp Quant Biol. 1978;42(Pt 2):755–772. doi: 10.1101/sqb.1978.042.01.076. [DOI] [PubMed] [Google Scholar]
  7. Harris M. Induction of thymidine kinase in enzyme-deficient Chinese hamster cells. Cell. 1982 Jun;29(2):483–492. doi: 10.1016/0092-8674(82)90165-9. [DOI] [PubMed] [Google Scholar]
  8. Hogan B. L., Taylor A., Adamson E. Cell interactions modulate embryonal carcinoma cell differentiation into parietal or visceral endoderm. Nature. 1981 May 21;291(5812):235–237. doi: 10.1038/291235a0. [DOI] [PubMed] [Google Scholar]
  9. Hurley C. K. Electrophoresis of histones: a modified Panyim and Chalkley system for slab gels. Anal Biochem. 1977 Jun;80(2):624–626. doi: 10.1016/0003-2697(77)90687-x. [DOI] [PubMed] [Google Scholar]
  10. Jakob H., Dubois P., Eisen H., Jacob F. Effets de l'hexaméthylènebisacétamide sur la différenciation de cellules de carcinome embryonnaire. C R Acad Sci Hebd Seances Acad Sci D. 1978 Jan;286(1):109–111. [PubMed] [Google Scholar]
  11. Jetten A. M., Jetten M. E. Possible role of retinoic acid binding protein in retinoid stimulation of embryonal carcinoma cell differentiation. Nature. 1979 Mar 8;278(5700):180–182. doi: 10.1038/278180a0. [DOI] [PubMed] [Google Scholar]
  12. Jetten A. M., Jetten M. E., Sherman M. I. Stimulation of differentiation of several murine embryonal carcinoma cell lines by retinoic acid. Exp Cell Res. 1979 Dec;124(2):381–391. doi: 10.1016/0014-4827(79)90213-1. [DOI] [PubMed] [Google Scholar]
  13. Kruh J. Effects of sodium butyrate, a new pharmacological agent, on cells in culture. Mol Cell Biochem. 1982 Feb 5;42(2):65–82. doi: 10.1007/BF00222695. [DOI] [PubMed] [Google Scholar]
  14. Kuff E. L., Fewell J. W. Induction of neural-like cells and acetylcholinesterase activity in cultures of F9 teratocarcinoma treated with retinoic acid and dibutyryl cyclic adenosine monophosphate. Dev Biol. 1980 Jun 1;77(1):103–115. doi: 10.1016/0012-1606(80)90459-5. [DOI] [PubMed] [Google Scholar]
  15. Leder A., Leder P. Butyric acid, a potent inducer of erythroid differentiation in cultured erythroleukemic cells. Cell. 1975 Jul;5(3):319–322. doi: 10.1016/0092-8674(75)90107-5. [DOI] [PubMed] [Google Scholar]
  16. Linney E., Levinson B. B. Teratocarcinoma differentiation: plasminogen activator activity associated with embryoid body formation. Cell. 1977 Feb;10(2):297–304. doi: 10.1016/0092-8674(77)90223-9. [DOI] [PubMed] [Google Scholar]
  17. Matthaei K. I., McCue P. A., Sherman M. I. Retinoid binding protein activities in murine embryonal carcinoma cells and their differentiated derivatives. Cancer Res. 1983 Jun;43(6):2862–2867. [PubMed] [Google Scholar]
  18. McCue P. A., Matthaei K. I., Taketo M., Sherman M. I. Differentiation-defective mutants of mouse embryonal carcinoma cells: response to hexamethylenebisacetamide and retinoic acid. Dev Biol. 1983 Apr;96(2):416–426. doi: 10.1016/0012-1606(83)90179-3. [DOI] [PubMed] [Google Scholar]
  19. McGhee J. D., Felsenfeld G. Nucleosome structure. Annu Rev Biochem. 1980;49:1115–1156. doi: 10.1146/annurev.bi.49.070180.005343. [DOI] [PubMed] [Google Scholar]
  20. Perry M., Chalkley R. Histone acetylation increases the solubility of chromatin and occurs sequentially over most of the chromatin. A novel model for the biological role of histone acetylation. J Biol Chem. 1982 Jul 10;257(13):7336–7347. [PubMed] [Google Scholar]
  21. Prasad K. N., Sinha P. K. Effect of sodium butyrate on mammalian cells in culture: a review. In Vitro. 1976 Feb;12(2):125–132. doi: 10.1007/BF02796360. [DOI] [PubMed] [Google Scholar]
  22. Riley D., Weintraub H. Conservative segregation of parental histones during replication in the presence of cycloheximide. Proc Natl Acad Sci U S A. 1979 Jan;76(1):328–332. doi: 10.1073/pnas.76.1.328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Schindler J., Matthaei K. I., Sherman M. I. Isolation and characterization of mouse mutant embryonal carcinoma cells which fail to differentiate in response to retinoic acid. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1077–1080. doi: 10.1073/pnas.78.2.1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schut H. A., Hughes E. H., Thorgeirsson S. S. Differential effects of dimethyl sulfoxide and sodium butyrate on alpha-fetoprotein, albumin, and transferrin production by rat hepatomas in culture. In Vitro. 1981 Apr;17(4):275–283. doi: 10.1007/BF02618138. [DOI] [PubMed] [Google Scholar]
  25. Sherman M. I., Paternoster M. L., Taketo M. Effects of arotinoids upon murine embryonal carcinoma cells. Cancer Res. 1983 Sep;43(9):4283–4290. [PubMed] [Google Scholar]
  26. Shewmaker C. K., Wagner T. E. Analysis of binding interactions between histone core complex and simian virus 40 DNA. A comparison of acetylated versus non-acetylated histone core complexes. Eur J Biochem. 1980 Jun;107(2):505–510. doi: 10.1111/j.1432-1033.1980.tb06057.x. [DOI] [PubMed] [Google Scholar]
  27. Solter D., Knowles B. B. Monoclonal antibody defining a stage-specific mouse embryonic antigen (SSEA-1). Proc Natl Acad Sci U S A. 1978 Nov;75(11):5565–5569. doi: 10.1073/pnas.75.11.5565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Speers W. C., Birdwell C. R., Dixon F. J. Chemically induced bidirectional differentiation of embryonal carcinoma cells in vitro. Am J Pathol. 1979 Dec;97(3):563–584. [PMC free article] [PubMed] [Google Scholar]
  29. Strickland S., Mahdavi V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell. 1978 Oct;15(2):393–403. doi: 10.1016/0092-8674(78)90008-9. [DOI] [PubMed] [Google Scholar]
  30. Strickland S., Smith K. K., Marotti K. R. Hormonal induction of differentiation in teratocarcinoma stem cells: generation of parietal endoderm by retinoic acid and dibutyryl cAMP. Cell. 1980 Sep;21(2):347–355. doi: 10.1016/0092-8674(80)90471-7. [DOI] [PubMed] [Google Scholar]
  31. Vavra K. J., Colavito-Shepanski M., Gorovsky M. A. Histone acetylation and the deoxyribonuclease I sensitivity of the Tetrahymena ribosomal gene. Biochemistry. 1982 Apr 13;21(8):1772–1781. doi: 10.1021/bi00537a012. [DOI] [PubMed] [Google Scholar]
  32. Vidali G., Boffa L. C., Allfrey V. G. Selective release of chromosomal proteins during limited DNAase 1 digestion of avian erythrocyte chromatin. Cell. 1977 Oct;12(2):409–415. doi: 10.1016/0092-8674(77)90117-9. [DOI] [PubMed] [Google Scholar]
  33. Vidali G., Boffa L. C., Bradbury E. M., Allfrey V. G. Butyrate suppression of histone deacetylation leads to accumulation of multiacetylated forms of histones H3 and H4 and increased DNase I sensitivity of the associated DNA sequences. Proc Natl Acad Sci U S A. 1978 May;75(5):2239–2243. doi: 10.1073/pnas.75.5.2239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Weintraub H., Groudine M. Chromosomal subunits in active genes have an altered conformation. Science. 1976 Sep 3;193(4256):848–856. doi: 10.1126/science.948749. [DOI] [PubMed] [Google Scholar]
  35. Weintraub H., Larsen A., Groudine M. Alpha-Globin-gene switching during the development of chicken embryos: expression and chromosome structure. Cell. 1981 May;24(2):333–344. doi: 10.1016/0092-8674(81)90323-8. [DOI] [PubMed] [Google Scholar]
  36. Weisbrod S., Weintraub H. Isolation of a subclass of nuclear proteins responsible for conferring a DNase I-sensitive structure on globin chromatin. Proc Natl Acad Sci U S A. 1979 Feb;76(2):630–634. doi: 10.1073/pnas.76.2.630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wu C., Wong Y. C., Elgin S. C. The chromatin structure of specific genes: II. Disruption of chromatin structure during gene activity. Cell. 1979 Apr;16(4):807–814. doi: 10.1016/0092-8674(79)90096-5. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES