DOI: 10.1073/pnas.0806501105. A gene regulatory network armature for T lymphocyte specification

A gene regulatory network armature for T lymphocyte specification

10.1073/pnas.0806501105

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Choice of a T lymphoid fate by hematopoietic progenitor cells depends on sustained Notch–Delta signaling combined with tightly regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification, tests of the short-term Notch dependence of these gene expression changes, and analyses of the effects of overexpression of two essential transcription factors, namely PU.1 and GATA-3. Quantitative expression measurements of >50 transcription factor and marker genes have been used to derive the principal components of regulatory change through which T cell precursors progress from primitive multipotency to T lineage commitment. Our analyses reveal separate contributions of Notch signaling, GATA-3 activity, and down-regulation of PU.1. Using BioTapestry ( www.BioTapestry.org ), the results have been assembled into a draft gene regulatory network for the specification of T cell precursors and the choice of T as opposed to myeloid/dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfi1 against Egr-2 and of TCF-1 against PU.1 as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose dependence of GATA-3 effects, the gene-specific modulation of PU.1 activity based on Notch activity, the lack of direct opposition between PU.1 and GATA-3, and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression.

Bibliography

Georgescu, C., Longabaugh, W. J. R., Scripture-Adams, D. D., David-Fung, E.-S., Yui, M. A., Zarnegar, M. A., Bolouri, H., & Rothenberg, E. V. (2008). A gene regulatory network armature for T lymphocyte specification. Proceedings of the National Academy of Sciences, 105(51), 20100â20105.

Authors 8

Constantin Georgescu (first)
William J. R. Longabaugh (additional)
Deirdre D. Scripture-Adams (additional)
Elizabeth-Sharon David-Fung (additional)
Mary A. Yui (additional)
Mark A. Zarnegar (additional)
Hamid Bolouri (additional)
Ellen V. Rothenberg (additional)

References 36 Referenced 79

10.1126/science.1140979
10.1016/j.cell.2006.06.052
10.1101/gad.1493506
10.1016/j.immuni.2007.06.005
10.1073/pnas.0500480102
10.1146/annurev.immunol.23.021704.115737
10.1111/j.0105-2896.2006.00355.x
10.1038/nri2232
10.4049/jimmunol.179.1.421
10.1146/annurev.immunol.23.021704.115715
10.1016/j.immuni.2005.11.012
10.1006/dbio.2002.0674
10.1073/pnas.0601188103
10.1038/ni1486
10.1016/j.ydbio.2007.02.036
10.1038/sj.onc.1205326
10.1146/annurev.immunol.24.021605.090742
10.1016/S1074-7613(02)00277-7
10.1016/S1074-7613(03)00176-6
10.1038/ng.2007.7
10.1038/ng1679
10.1016/S1074-7613(02)00474-0
10.1101/gad.1298305
10.1084/jem.20060268
10.1016/j.ydbio.2005.04.023
10.1016/j.ydbio.2006.02.051
10.1038/sj.onc.1205324
10.1084/jem.20061020
10.4049/jimmunol.173.9.5381
10.1073/pnas.0603728103
10.4049/jimmunol.177.1.109
10.1182/blood-2006-08-043331
10.1038/ni1260
10.1016/j.immuni.2008.05.015
10.1084/jem.20061959
ES David-Fung, et al., Transcription factor expression dynamics of early T-lymphocyte specification and commitment. Dev Biol, 2008). / Dev Biol / Transcription factor expression dynamics of early T-lymphocyte specification and commitment by David-Fung ES (2008)

Dates

Type	When
Created	16 years, 8 months ago (Dec. 22, 2008, 9:10 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 6:06 p.m.)
Indexed	1 month ago (July 26, 2025, 4:44 a.m.)
Issued	16 years, 8 months ago (Dec. 23, 2008)
Published	16 years, 8 months ago (Dec. 23, 2008)
Published Online	16 years, 8 months ago (Dec. 23, 2008)
Published Print	16 years, 8 months ago (Dec. 23, 2008)

Funders 0

None

BibTeX

@article{Georgescu_2008, title={A gene regulatory network armature for T lymphocyte specification}, volume={105}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0806501105}, DOI={10.1073/pnas.0806501105}, number={51}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Georgescu, Constantin and Longabaugh, William J. R. and Scripture-Adams, Deirdre D. and David-Fung, Elizabeth-Sharon and Yui, Mary A. and Zarnegar, Mark A. and Bolouri, Hamid and Rothenberg, Ellen V.}, year={2008}, month=dec, pages={20100–20105} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        26
      ]
    ],
    "date-time": "2025-07-26T08:44:55Z",
    "timestamp": 1753519495530
  },
  "reference-count": 36,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "51",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2008,
        12,
        23
      ]
    ]
  },
  "abstract": "<jats:p>\n            Choice of a T lymphoid fate by hematopoietic progenitor cells depends on sustained Notch\u2013Delta signaling combined with tightly regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification, tests of the short-term Notch dependence of these gene expression changes, and analyses of the effects of overexpression of two essential transcription factors, namely PU.1 and GATA-3. Quantitative expression measurements of &gt;50 transcription factor and marker genes have been used to derive the principal components of regulatory change through which T cell precursors progress from primitive multipotency to T lineage commitment. Our analyses reveal separate contributions of Notch signaling, GATA-3 activity, and down-regulation of PU.1. Using BioTapestry (\n            <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"http://www.BioTapestry.org\">www.BioTapestry.org</jats:ext-link>\n            ), the results have been assembled into a draft gene regulatory network for the specification of T cell precursors and the choice of T as opposed to myeloid/dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfi1 against Egr-2 and of TCF-1 against PU.1 as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose dependence of GATA-3 effects, the gene-specific modulation of PU.1 activity based on Notch activity, the lack of direct opposition between PU.1 and GATA-3, and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression.\n          </jats:p>",
  "DOI": "10.1073/pnas.0806501105",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2008,
        12,
        23
      ]
    ],
    "date-time": "2008-12-23T02:10:18Z",
    "timestamp": 1229998218000
  },
  "page": "20100-20105",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 79,
  "title": "A gene regulatory network armature for T lymphocyte specification",
  "prefix": "10.1073",
  "volume": "105",
  "author": [
    {
      "given": "Constantin",
      "family": "Georgescu",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125; and"
        }
      ]
    },
    {
      "given": "William J. R.",
      "family": "Longabaugh",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103"
        }
      ]
    },
    {
      "given": "Deirdre D.",
      "family": "Scripture-Adams",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125; and"
        }
      ]
    },
    {
      "given": "Elizabeth-Sharon",
      "family": "David-Fung",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125; and"
        }
      ]
    },
    {
      "given": "Mary A.",
      "family": "Yui",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125; and"
        }
      ]
    },
    {
      "given": "Mark A.",
      "family": "Zarnegar",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125; and"
        }
      ]
    },
    {
      "given": "Hamid",
      "family": "Bolouri",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125; and"
        },
        {
          "name": "Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103"
        }
      ]
    },
    {
      "given": "Ellen V.",
      "family": "Rothenberg",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125; and"
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        2008,
        12,
        23
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_3_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.1140979"
    },
    {
      "key": "e_1_3_3_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.cell.2006.06.052"
    },
    {
      "key": "e_1_3_3_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1101/gad.1493506"
    },
    {
      "key": "e_1_3_3_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.immuni.2007.06.005"
    },
    {
      "key": "e_1_3_3_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.0500480102"
    },
    {
      "key": "e_1_3_3_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.immunol.23.021704.115737"
    },
    {
      "key": "e_1_3_3_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1111/j.0105-2896.2006.00355.x"
    },
    {
      "key": "e_1_3_3_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nri2232"
    },
    {
      "key": "e_1_3_3_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.4049/jimmunol.179.1.421"
    },
    {
      "key": "e_1_3_3_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.immunol.23.021704.115715"
    },
    {
      "key": "e_1_3_3_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.immuni.2005.11.012"
    },
    {
      "key": "e_1_3_3_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/dbio.2002.0674"
    },
    {
      "key": "e_1_3_3_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.0601188103"
    },
    {
      "key": "e_1_3_3_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ni1486"
    },
    {
      "key": "e_1_3_3_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.ydbio.2007.02.036"
    },
    {
      "key": "e_1_3_3_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.onc.1205326"
    },
    {
      "key": "e_1_3_3_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.immunol.24.021605.090742"
    },
    {
      "key": "e_1_3_3_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S1074-7613(02)00277-7"
    },
    {
      "key": "e_1_3_3_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S1074-7613(03)00176-6"
    },
    {
      "key": "e_1_3_3_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ng.2007.7"
    },
    {
      "key": "e_1_3_3_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ng1679"
    },
    {
      "key": "e_1_3_3_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S1074-7613(02)00474-0"
    },
    {
      "key": "e_1_3_3_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1101/gad.1298305"
    },
    {
      "key": "e_1_3_3_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1084/jem.20060268"
    },
    {
      "key": "e_1_3_3_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.ydbio.2005.04.023"
    },
    {
      "key": "e_1_3_3_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.ydbio.2006.02.051"
    },
    {
      "key": "e_1_3_3_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.onc.1205324"
    },
    {
      "key": "e_1_3_3_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1084/jem.20061020"
    },
    {
      "key": "e_1_3_3_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.4049/jimmunol.173.9.5381"
    },
    {
      "key": "e_1_3_3_30_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.0603728103"
    },
    {
      "key": "e_1_3_3_31_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.4049/jimmunol.177.1.109"
    },
    {
      "key": "e_1_3_3_32_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood-2006-08-043331"
    },
    {
      "key": "e_1_3_3_33_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ni1260"
    },
    {
      "key": "e_1_3_3_34_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.immuni.2008.05.015"
    },
    {
      "key": "e_1_3_3_35_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1084/jem.20061959"
    },
    {
      "key": "e_1_3_3_36_2",
      "article-title": "Transcription factor expression dynamics of early T-lymphocyte specification and commitment",
      "author": "David-Fung ES",
      "year": "2008",
      "unstructured": "ES David-Fung, et al., Transcription factor expression dynamics of early T-lymphocyte specification and commitment. Dev Biol, 2008).",
      "journal-title": "Dev Biol"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.0806501105",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        12
      ]
    ],
    "date-time": "2022-04-12T22:06:55Z",
    "timestamp": 1649801215000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.0806501105"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2008,
        12,
        23
      ]
    ]
  },
  "references-count": 36,
  "journal-issue": {
    "issue": "51",
    "published-print": {
      "date-parts": [
        [
          2008,
          12,
          23
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.0806501105"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.0806501105",
  "relation": {
    "has-review": [
      {
        "id-type": "doi",
        "id": "10.3410/f.1139085.596198",
        "asserted-by": "object"
      }
    ]
  },
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        2008,
        12,
        23
      ]
    ]
  },
  "assertion": [
    {
      "value": "2008-07-06",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2008-12-23",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}