The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes

Yi Qing He, Elissa Sutcliffe, Karen Bunting, Jasmine Li, Katharine Goodall, Ivan Poon, Mark Hulett, Craig Freeman, Anjum Zafar, Russell McInnes, Taya Toshiki, Christopher Parish, Sudha Rao

    Research output: Contribution to journalArticle

    26 Citations (Scopus)

    Abstract

    The methylation of histones is a fundamental epigenetic process regulating gene expression programs in mammalian cells. Dysregulated patterns of histone methylation are directly implicated in malignant transformation. Here, we report the unexpected finding that the invasive extracellular matrix degrading endoglycosidase heparanase enters the nucleus of activated human T lymphocytes and regulates the transcription of a cohort of inducible immune response genes by controlling histone H3 methylation patterns. It was found that nuclear heparanase preferentially associates with euchromatin. Genome-wide ChIP-on-chip analyses showed that heparanase is recruited to both the promoter and transcribed regions of a distinct cohort of transcriptionally active genes. Knockdown and overexpression of the heparanase gene also showed that chromatin-bound heparanase is a prerequisite for the transcription of a subset of inducible immune response genes in activated T cells. Furthermore, the actions of heparanase seem to influence gene transcription by associating with the demethylase LSD1, preventing recruitment of the methylase MLL and thereby modifying histone H3 methylation patterns. These data indicate that heparanase belongs to an emerging class of proteins that play an important role in regulating transcription in addition to their well-recognized extra-nuclear functions
    Original languageEnglish
    Pages (from-to)130-145
    Number of pages16
    JournalTranscription
    Volume3
    Issue number3
    DOIs
    Publication statusPublished - 2012

    Fingerprint

    Methylation
    T-cells
    Glycoside Hydrolases
    Chromatin
    Genes
    T-Lymphocytes
    Transcription
    Histones
    Enzymes
    Genetic Epigenesis
    Euchromatin
    heparanase
    Genetic Promoter Regions
    Gene expression
    Extracellular Matrix
    Cells
    Genome
    Gene Expression

    Cite this

    He, Yi Qing ; Sutcliffe, Elissa ; Bunting, Karen ; Li, Jasmine ; Goodall, Katharine ; Poon, Ivan ; Hulett, Mark ; Freeman, Craig ; Zafar, Anjum ; McInnes, Russell ; Toshiki, Taya ; Parish, Christopher ; Rao, Sudha. / The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes. In: Transcription. 2012 ; Vol. 3, No. 3. pp. 130-145.
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    abstract = "The methylation of histones is a fundamental epigenetic process regulating gene expression programs in mammalian cells. Dysregulated patterns of histone methylation are directly implicated in malignant transformation. Here, we report the unexpected finding that the invasive extracellular matrix degrading endoglycosidase heparanase enters the nucleus of activated human T lymphocytes and regulates the transcription of a cohort of inducible immune response genes by controlling histone H3 methylation patterns. It was found that nuclear heparanase preferentially associates with euchromatin. Genome-wide ChIP-on-chip analyses showed that heparanase is recruited to both the promoter and transcribed regions of a distinct cohort of transcriptionally active genes. Knockdown and overexpression of the heparanase gene also showed that chromatin-bound heparanase is a prerequisite for the transcription of a subset of inducible immune response genes in activated T cells. Furthermore, the actions of heparanase seem to influence gene transcription by associating with the demethylase LSD1, preventing recruitment of the methylase MLL and thereby modifying histone H3 methylation patterns. These data indicate that heparanase belongs to an emerging class of proteins that play an important role in regulating transcription in addition to their well-recognized extra-nuclear functions",
    author = "He, {Yi Qing} and Elissa Sutcliffe and Karen Bunting and Jasmine Li and Katharine Goodall and Ivan Poon and Mark Hulett and Craig Freeman and Anjum Zafar and Russell McInnes and Taya Toshiki and Christopher Parish and Sudha Rao",
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    He, YQ, Sutcliffe, E, Bunting, K, Li, J, Goodall, K, Poon, I, Hulett, M, Freeman, C, Zafar, A, McInnes, R, Toshiki, T, Parish, C & Rao, S 2012, 'The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes', Transcription, vol. 3, no. 3, pp. 130-145. https://doi.org/10.4161/trns.19998

    The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes. / He, Yi Qing; Sutcliffe, Elissa; Bunting, Karen; Li, Jasmine; Goodall, Katharine; Poon, Ivan; Hulett, Mark; Freeman, Craig; Zafar, Anjum; McInnes, Russell; Toshiki, Taya; Parish, Christopher; Rao, Sudha.

    In: Transcription, Vol. 3, No. 3, 2012, p. 130-145.

    Research output: Contribution to journalArticle

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    AU - Poon, Ivan

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    AU - Freeman, Craig

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    AU - Parish, Christopher

    AU - Rao, Sudha

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    AB - The methylation of histones is a fundamental epigenetic process regulating gene expression programs in mammalian cells. Dysregulated patterns of histone methylation are directly implicated in malignant transformation. Here, we report the unexpected finding that the invasive extracellular matrix degrading endoglycosidase heparanase enters the nucleus of activated human T lymphocytes and regulates the transcription of a cohort of inducible immune response genes by controlling histone H3 methylation patterns. It was found that nuclear heparanase preferentially associates with euchromatin. Genome-wide ChIP-on-chip analyses showed that heparanase is recruited to both the promoter and transcribed regions of a distinct cohort of transcriptionally active genes. Knockdown and overexpression of the heparanase gene also showed that chromatin-bound heparanase is a prerequisite for the transcription of a subset of inducible immune response genes in activated T cells. Furthermore, the actions of heparanase seem to influence gene transcription by associating with the demethylase LSD1, preventing recruitment of the methylase MLL and thereby modifying histone H3 methylation patterns. These data indicate that heparanase belongs to an emerging class of proteins that play an important role in regulating transcription in addition to their well-recognized extra-nuclear functions

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