DOI: 10.1073/pnas.1436338100. MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein

MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein

10.1073/pnas.1436338100

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The MLL ( mixed-lineage leukemia ) gene is involved in many chromosomal translocations associated with acute myeloid and lymphoid leukemia. We previously identified a transcriptional repression domain in MLL, which contains a region with homology to DNA methyltransferase. In chromosomal translocations, the MLL repression domain is retained in the leukemogenic fusion protein and is required for transforming activity of MLL fusion proteins. We explored the mechanism of action of the MLL repression domain. Histone deacetylase 1 interacts with the MLL repression domain, partially mediating its activity; binding of Cyp33 to the adjacent MLL-PHD domain potentiates this binding. Because the MLL repression domain activity was only partially relieved with the histone deacetylase inhibitor trichostatin A, we explored other protein interactions with this domain. Polycomb group proteins HPC2 and BMI-1 and the corepressor C-terminal-binding protein also bind the MLL repression domain. Expression of exogenous BMI-1 potentiates MLL repression domain activity. Functional antagonism between Mll and Bmi-1 has been shown genetically in murine knockout models for Mll and Bmi-1 . Our new data suggest a model whereby recruitment of BMI-1 to the MLL protein may be able to modulate its function. Furthermore, repression mediated by histone deacetylases and that mediated by polycomb group proteins may act either independently or together for MLL function in vivo .

Authors 4

Zhen-Biao Xia (first)
Melanie Anderson (additional)
Manuel O. Diaz (additional)
Nancy J. Zeleznik-Le (additional)

References 43 Referenced 159

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Dates

Type	When
Created	22 years, 1 month ago (July 8, 2003, 3:18 p.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 12:13 a.m.)
Indexed	2 weeks ago (Aug. 19, 2025, 6:09 a.m.)
Issued	22 years, 2 months ago (June 26, 2003)
Published	22 years, 2 months ago (June 26, 2003)
Published Online	22 years, 2 months ago (June 26, 2003)
Published Print	22 years, 1 month ago (July 8, 2003)

Funders 0

None

BibTeX

@article{Xia_2003, title={MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.1436338100}, DOI={10.1073/pnas.1436338100}, number={14}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Xia, Zhen-Biao and Anderson, Melanie and Diaz, Manuel O. and Zeleznik-Le, Nancy J.}, year={2003}, month=jun, pages={8342–8347} }

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  "abstract": "<jats:p>\n            The\n            <jats:italic>MLL</jats:italic>\n            (\n            <jats:italic>mixed-lineage leukemia</jats:italic>\n            ) gene is involved in many\n chromosomal translocations associated with acute myeloid and lymphoid\n leukemia. We previously identified a transcriptional repression domain in MLL,\n which contains a region with homology to DNA methyltransferase. In chromosomal\n translocations, the MLL repression domain is retained in the leukemogenic\n fusion protein and is required for transforming activity of MLL fusion\n proteins. We explored the mechanism of action of the MLL repression domain.\n Histone deacetylase 1 interacts with the MLL repression domain, partially\n mediating its activity; binding of Cyp33 to the adjacent MLL-PHD domain\n potentiates this binding. Because the MLL repression domain activity was only\n partially relieved with the histone deacetylase inhibitor trichostatin A, we\n explored other protein interactions with this domain. Polycomb group proteins\n HPC2 and BMI-1 and the corepressor C-terminal-binding protein also bind the\n MLL repression domain. Expression of exogenous BMI-1 potentiates MLL\n repression domain activity. Functional antagonism between Mll and Bmi-1 has\n been shown genetically in murine knockout models for\n            <jats:italic>Mll</jats:italic>\n            and\n            <jats:italic>Bmi-1</jats:italic>\n            . Our new data suggest a model whereby recruitment of BMI-1 to\n the MLL protein may be able to modulate its function. Furthermore, repression\n mediated by histone deacetylases and that mediated by polycomb group proteins\n may act either independently or together for MLL function\n            <jats:italic>in\n vivo</jats:italic>\n            .\n          </jats:p>",
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