DOI: 10.1073/pnas.96.25.14372. Mammalian <i>Trithorax</i> and <i>Polycomb</i> -group homologues are antagonistic regulators of homeotic development

Mammalian Trithorax and Polycomb -group homologues are antagonistic regulators of homeotic development

10.1073/pnas.96.25.14372

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Control of cell identity during development is specified in large part by the unique expression patterns of multiple homeobox-containing ( Hox ) genes in specific segments of an embryo. Trithorax and Polycomb-group (Trx-G and Pc-G) proteins in Drosophila maintain Hox expression or repression, respectively. Mixed lineage leukemia (MLL) is frequently involved in chromosomal translocations associated with acute leukemia and is the one established mammalian homologue of Trx . Bmi-1 was first identified as a collaborator in c-myc -induced murine lymphomagenesis and is homologous to the Drosophila Pc-G member Posterior sex combs . Here, we note the axial-skeletal transformations and altered Hox expression patterns of Mll -deficient and Bmi-1 -deficient mice were normalized when both Mll and Bmi-1 were deleted, demonstrating their antagonistic role in determining segmental identity. Embryonic fibroblasts from Mll -deficient compared with Bmi-1 -deficient mice demonstrate reciprocal regulation of Hox genes as well as an integrated Hoxc8 -lacZ reporter construct. Reexpression of MLL was able to overcome repression, rescuing expression of Hoxc8 -lacZ in Mll -deficient cells. Consistent with this, MLL and BMI-I display discrete subnuclear colocalization. Although Drosophila Pc-G and Trx-G members have been shown to maintain a previously established transcriptional pattern, we demonstrate that MLL can also dynamically regulate a target Hox gene.

Bibliography

Hanson, R. D., Hess, J. L., Yu, B. D., Ernst, P., van Lohuizen, M., Berns, A., van der Lugt, N. M. T., Shashikant, C. S., Ruddle, F. H., Seto, M., & Korsmeyer, S. J. (1999). Mammalian Trithorax and Polycomb -group homologues are antagonistic regulators of homeotic development. Proceedings of the National Academy of Sciences, 96(25), 14372â14377.

Authors 11

Robin D. Hanson (first)
Jay L. Hess (additional)
Benjamin D. Yu (additional)
Patricia Ernst (additional)
Maarten van Lohuizen (additional)
Anton Berns (additional)
Nathalie M. T. van der Lugt (additional)
Cooduvalli S. Shashikant (additional)
Frank H. Ruddle (additional)
Masao Seto (additional)
Stanley J. Korsmeyer (additional)

References 30 Referenced 192

10.1146/annurev.genet.32.1.495
10.1128/mcb.13.10.6357-6366.1993
10.1016/S0168-9525(97)01133-5
10.1146/annurev.ge.29.120195.001445
10.1016/S0168-9525(00)89081-2
10.1016/0925-4773(91)90062-B
10.1016/0925-4773(95)00393-F
10.1242/dev.120.7.1907
10.1002/j.1460-2075.1995.tb07197.x
10.1002/j.1460-2075.1992.tb05364.x
10.1242/dev.114.4.921
10.1016/0092-8674(91)90383-A
10.1016/0092-8674(91)90382-9
10.1101/gad.11.2.226
10.1093/emboj/16.11.3219
10.1016/S0925-4773(96)00570-9
10.1038/374724a0
10.1038/378505a0
10.1101/gad.8.7.757
10.1073/pnas.95.18.10632
10.1016/0092-8674(91)90574-I
10.1016/0076-6879(93)25025-W
10.1016/0378-1119(91)90434-D
T Joh, Y Kagami, K Yamamoto, T Segawa, Takizawa, T Takahashi, R Ueda, M Seto Oncogene 13, 1945–1953 (1996). / Oncogene by Joh T (1996)
10.1128/mcb.4.11.2406-2412.1984
10.1073/pnas.93.6.2426
10.1242/dev.121.12.4339
10.1038/306591a0
10.1182/blood.V80.10.2445.2445
10.1182/blood.V91.4.1216

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:39 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 4:21 p.m.)
Indexed	1 week, 4 days ago (Aug. 21, 2025, 1:37 p.m.)
Issued	25 years, 8 months ago (Dec. 7, 1999)
Published	25 years, 8 months ago (Dec. 7, 1999)
Published Online	25 years, 8 months ago (Dec. 7, 1999)
Published Print	25 years, 8 months ago (Dec. 7, 1999)

Funders 0

None

BibTeX

@article{Hanson_1999, title={Mammalian Trithorax and Polycomb -group homologues are antagonistic regulators of homeotic development}, volume={96}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.96.25.14372}, DOI={10.1073/pnas.96.25.14372}, number={25}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Hanson, Robin D. and Hess, Jay L. and Yu, Benjamin D. and Ernst, Patricia and van Lohuizen, Maarten and Berns, Anton and van der Lugt, Nathalie M. T. and Shashikant, Cooduvalli S. and Ruddle, Frank H. and Seto, Masao and Korsmeyer, Stanley J.}, year={1999}, month=dec, pages={14372–14377} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        8,
        21
      ]
    ],
    "date-time": "2025-08-21T17:37:29Z",
    "timestamp": 1755797849863
  },
  "reference-count": 30,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "25",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        1999,
        12,
        7
      ]
    ]
  },
  "abstract": "<jats:p>\n            Control of cell identity during development is specified in large part by the unique expression patterns of multiple homeobox-containing (\n            <jats:italic>Hox</jats:italic>\n            ) genes in specific segments of an embryo. Trithorax and Polycomb-group (Trx-G and Pc-G) proteins in\n            <jats:italic>Drosophila</jats:italic>\n            maintain\n            <jats:italic>Hox</jats:italic>\n            expression or repression, respectively. Mixed lineage leukemia (MLL) is frequently involved in chromosomal translocations associated with acute leukemia and is the one established mammalian homologue of\n            <jats:italic>Trx</jats:italic>\n            .\n            <jats:italic>Bmi-1</jats:italic>\n            was first identified as a collaborator in\n            <jats:italic>c-myc</jats:italic>\n            -induced murine lymphomagenesis and is homologous to the Drosophila Pc-G member\n            <jats:italic>Posterior sex combs</jats:italic>\n            . Here, we note the axial-skeletal transformations and altered\n            <jats:italic>Hox</jats:italic>\n            expression patterns of\n            <jats:italic>Mll</jats:italic>\n            -deficient and\n            <jats:italic>Bmi-1</jats:italic>\n            -deficient mice were normalized when both\n            <jats:italic>Mll</jats:italic>\n            and\n            <jats:italic>Bmi-1</jats:italic>\n            were deleted, demonstrating their antagonistic role in determining segmental identity. Embryonic fibroblasts from\n            <jats:italic>Mll</jats:italic>\n            -deficient compared with\n            <jats:italic>Bmi-1</jats:italic>\n            -deficient mice demonstrate reciprocal regulation of\n            <jats:italic>Hox</jats:italic>\n            genes as well as an integrated\n            <jats:italic>Hoxc8</jats:italic>\n            -lacZ reporter construct. Reexpression of\n            <jats:italic>MLL</jats:italic>\n            was able to overcome repression, rescuing expression of\n            <jats:italic>Hoxc8</jats:italic>\n            -lacZ in\n            <jats:italic>Mll</jats:italic>\n            -deficient cells. Consistent with this, MLL and BMI-I display discrete subnuclear colocalization. Although\n            <jats:italic>Drosophila</jats:italic>\n            Pc-G and Trx-G members have been shown to maintain a previously established transcriptional pattern, we demonstrate that MLL can also dynamically regulate a target\n            <jats:italic>Hox</jats:italic>\n            gene.\n          </jats:p>",
  "DOI": "10.1073/pnas.96.25.14372",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2002,
        7,
        26
      ]
    ],
    "date-time": "2002-07-26T14:39:15Z",
    "timestamp": 1027694355000
  },
  "page": "14372-14377",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 192,
  "title": "Mammalian\n            <i>Trithorax</i>\n            and\n            <i>Polycomb</i>\n            -group homologues are antagonistic regulators of homeotic development",
  "prefix": "10.1073",
  "volume": "96",
  "author": [
    {
      "given": "Robin D.",
      "family": "Hanson",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Jay L.",
      "family": "Hess",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Benjamin D.",
      "family": "Yu",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Patricia",
      "family": "Ernst",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Maarten",
      "family": "van Lohuizen",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Anton",
      "family": "Berns",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Nathalie M. T.",
      "family": "van der Lugt",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Cooduvalli S.",
      "family": "Shashikant",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Frank H.",
      "family": "Ruddle",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Masao",
      "family": "Seto",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    },
    {
      "given": "Stanley J.",
      "family": "Korsmeyer",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Howard Hughes Medical Institute, Departments of Medicine, Pediatrics, and Pathology, Washington University School of Medicine, St. Louis, MO 63110; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Laboratory of Chemotherapy, Aichi Cancer Center Research Institute,..."
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        1999,
        12,
        7
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_3_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.genet.32.1.495"
    },
    {
      "key": "e_1_3_3_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/mcb.13.10.6357-6366.1993"
    },
    {
      "key": "e_1_3_3_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0168-9525(97)01133-5"
    },
    {
      "key": "e_1_3_3_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.ge.29.120195.001445"
    },
    {
      "key": "e_1_3_3_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0168-9525(00)89081-2"
    },
    {
      "key": "e_1_3_3_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0925-4773(91)90062-B"
    },
    {
      "key": "e_1_3_3_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0925-4773(95)00393-F"
    },
    {
      "key": "e_1_3_3_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1242/dev.120.7.1907"
    },
    {
      "key": "e_1_3_3_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/j.1460-2075.1995.tb07197.x"
    },
    {
      "key": "e_1_3_3_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/j.1460-2075.1992.tb05364.x"
    },
    {
      "key": "e_1_3_3_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1242/dev.114.4.921"
    },
    {
      "key": "e_1_3_3_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(91)90383-A"
    },
    {
      "key": "e_1_3_3_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(91)90382-9"
    },
    {
      "key": "e_1_3_3_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1101/gad.11.2.226"
    },
    {
      "key": "e_1_3_3_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/emboj/16.11.3219"
    },
    {
      "key": "e_1_3_3_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0925-4773(96)00570-9"
    },
    {
      "key": "e_1_3_3_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/374724a0"
    },
    {
      "key": "e_1_3_3_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/378505a0"
    },
    {
      "key": "e_1_3_3_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1101/gad.8.7.757"
    },
    {
      "key": "e_1_3_3_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.95.18.10632"
    },
    {
      "key": "e_1_3_3_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(91)90574-I"
    },
    {
      "key": "e_1_3_3_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0076-6879(93)25025-W"
    },
    {
      "key": "e_1_3_3_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0378-1119(91)90434-D"
    },
    {
      "key": "e_1_3_3_24_2",
      "first-page": "1945",
      "volume": "13",
      "author": "Joh T",
      "year": "1996",
      "unstructured": "T Joh, Y Kagami, K Yamamoto, T Segawa, Takizawa, T Takahashi, R Ueda, M Seto Oncogene 13, 1945\u20131953 (1996).",
      "journal-title": "Oncogene"
    },
    {
      "key": "e_1_3_3_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/mcb.4.11.2406-2412.1984"
    },
    {
      "key": "e_1_3_3_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.93.6.2426"
    },
    {
      "key": "e_1_3_3_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1242/dev.121.12.4339"
    },
    {
      "key": "e_1_3_3_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/306591a0"
    },
    {
      "key": "e_1_3_3_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V80.10.2445.2445"
    },
    {
      "key": "e_1_3_3_30_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V91.4.1216"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.96.25.14372",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        13
      ]
    ],
    "date-time": "2022-04-13T20:21:09Z",
    "timestamp": 1649881269000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.96.25.14372"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        1999,
        12,
        7
      ]
    ]
  },
  "references-count": 30,
  "journal-issue": {
    "issue": "25",
    "published-print": {
      "date-parts": [
        [
          1999,
          12,
          7
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.96.25.14372"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.96.25.14372",
  "relation": {},
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        1999,
        12,
        7
      ]
    ]
  },
  "assertion": [
    {
      "value": "1999-10-05",
      "order": 1,
      "name": "accepted",
      "label": "Accepted",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "1999-12-07",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}