Gfi1 coordinates epigenetic repression of p21Cip/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1
- PMID: 16287849
- PMCID: PMC1291230
- DOI: 10.1128/MCB.25.23.10338-10351.2005
Gfi1 coordinates epigenetic repression of p21Cip/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1
Abstract
The growth factor independent 1 (Gfi1) transcriptional regulator oncoprotein plays a crucial role in hematopoietic, inner ear, and pulmonary neuroendocrine cell development and governs cell processes as diverse as self-renewal of hematopoietic stem cells, proliferation, apoptosis, differentiation, cell fate specification, and oncogenesis. However, the molecular basis of its transcriptional functions has remained elusive. Here we show that Gfi1 recruits the histone lysine methyltransferase G9a and the histone deacetylase 1 (HDAC1) in order to modify the chromatin of genes targeted for repression by Gfi1. G9a and HDAC1 are both in a repressive complex assembled by Gfi1. Endogenous Gfi1 colocalizes with G9a, HDAC1, and K9-dimethylated histone H3. Gfi1 associates with G9a and HDAC1 on the promoter of the cell cycle regulator p21Cip/WAF1, resulting in an increase in K9 dimethylation at histone H3. Silencing of Gfi1 expression in myeloid cells reverses G9a and HDAC1 recruitment to p21Cip/WAF1 and elevates its expression. These findings highlight the role of epigenetics in the regulation of development and oncogenesis by Gfi1.
Figures
![FIG. 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb0230555480001.gif)
![FIG. 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb0230555480002.gif)
![FIG. 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb0230555480002.gif)
![FIG. 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb0230555480003.gif)
![FIG. 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb0230555480004.gif)
![FIG. 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb023055548005a.gif)
![FIG. 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb023055548005a.gif)
![FIG. 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb0230555480006.gif)
![FIG. 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb0230555480007.gif)
![FIG. 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1291230/bin/zmb0230555480007.gif)
Similar articles
-
Epigenetic regulation of protein-coding and microRNA genes by the Gfi1-interacting tumor suppressor PRDM5.Mol Cell Biol. 2007 Oct;27(19):6889-902. doi: 10.1128/MCB.00762-07. Epub 2007 Jul 16. Mol Cell Biol. 2007. PMID: 17636019 Free PMC article.
-
CCAAT displacement protein/cut homolog recruits G9a histone lysine methyltransferase to repress transcription.Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11257-62. doi: 10.1073/pnas.0401343101. Epub 2004 Jul 21. Proc Natl Acad Sci U S A. 2004. PMID: 15269344 Free PMC article.
-
Hypoxic silencing of tumor suppressor RUNX3 by histone modification in gastric cancer cells.Oncogene. 2009 Jan 15;28(2):184-94. doi: 10.1038/onc.2008.377. Epub 2008 Oct 13. Oncogene. 2009. PMID: 18850007
-
[The roles of histone lysine methylation in epigenetic regulation].Yi Chuan. 2007 Apr;29(4):387-92. doi: 10.1360/yc-007-0387. Yi Chuan. 2007. PMID: 17548299 Review. Chinese.
-
G9a - An Appealing Antineoplastic Target.Curr Cancer Drug Targets. 2017;17(6):555-568. doi: 10.2174/1568009616666160512145303. Curr Cancer Drug Targets. 2017. PMID: 27174055 Review.
Cited by
-
Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy.Blood. 2023 Dec 21;142(25):2175-2191. doi: 10.1182/blood.2022015752. Blood. 2023. PMID: 37756525 Free PMC article.
-
Activation of lineage competence in hemogenic endothelium precedes the formation of hematopoietic stem cell heterogeneity.Cell Res. 2023 Jun;33(6):448-463. doi: 10.1038/s41422-023-00797-0. Epub 2023 Apr 4. Cell Res. 2023. PMID: 37016019 Free PMC article.
-
Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites.Front Cell Dev Biol. 2022 Nov 7;10:1016367. doi: 10.3389/fcell.2022.1016367. eCollection 2022. Front Cell Dev Biol. 2022. PMID: 36420143 Free PMC article.
-
Hematopoietic transcription factor GFI1 promotes anchorage independence by sustaining ERK activity in cancer cells.J Clin Invest. 2022 Sep 1;132(17):e149551. doi: 10.1172/JCI149551. J Clin Invest. 2022. PMID: 35819844 Free PMC article.
-
Epigenetic Crosstalk between Malignant Plasma Cells and the Tumour Microenvironment in Multiple Myeloma.Cancers (Basel). 2022 May 24;14(11):2597. doi: 10.3390/cancers14112597. Cancers (Basel). 2022. PMID: 35681577 Free PMC article. Review.
References
-
- Ayyanathan, K., M. S. Lechner, P. Bell, G. G. Maul, D. C. Schultz, Y. Yamada, K. Tanaka, K. Torigoe, and F. J. Rauscher III. 2003. Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev. 17:1855-1869. - PMC - PubMed
-
- Benson, K. F., F. Q. Li, R. E. Person, D. Albani, Z. Duan, J. Wechsler, K. Meade-White, K. Williams, G. M. Acland, G. Niemeyer, C. D. Lothrop, and M. Horwitz. 2003. Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase. Nat. Genet. 35:90-96. - PubMed
-
- Berger, S. L. 2002. Histone modifications in transcriptional regulation. Curr. Opin. Genet. Dev. 12:142-148. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Miscellaneous