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

27 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",
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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 - He, Yi Qing

AU - Sutcliffe, Elissa

AU - Bunting, Karen

AU - Li, Jasmine

AU - Goodall, Katharine

AU - Poon, Ivan

AU - Hulett, Mark

AU - Freeman, Craig

AU - Zafar, Anjum

AU - McInnes, Russell

AU - Toshiki, Taya

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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