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 L Sutcliffe, Karen L. Bunting, Jasmine Li, Katharine J. Goodall, Ivan K A Poon, Mark D. Hulett, Craig Freeman, Anjum Zafar, Russell L. McInnes, Toshiki Taya, Christopher R Parish, Sudha Rao

Research output: Contribution to journalArticleResearchpeer-review

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 (Austin)
Volume3
Issue number3
Publication statusPublished - May 2012
Externally publishedYes

Keywords

  • Chromatin
  • Heparanase
  • Histone methylation
  • Immune response genes
  • Inducible genes
  • T lymphocytes
  • Transcription

Cite this

He, Yi Qing ; Sutcliffe, Elissa L ; Bunting, Karen L. ; Li, Jasmine ; Goodall, Katharine J. ; Poon, Ivan K A ; Hulett, Mark D. ; Freeman, Craig ; Zafar, Anjum ; McInnes, Russell L. ; Taya, Toshiki ; Parish, Christopher R ; 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 (Austin). 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.",
keywords = "Chromatin, Heparanase, Histone methylation, Immune response genes, Inducible genes, T lymphocytes, Transcription",
author = "He, {Yi Qing} and Sutcliffe, {Elissa L} and Bunting, {Karen L.} and Jasmine Li and Goodall, {Katharine J.} and Poon, {Ivan K A} and Hulett, {Mark D.} and Craig Freeman and Anjum Zafar and McInnes, {Russell L.} and Toshiki Taya and Parish, {Christopher R} and Sudha Rao",
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He, YQ, Sutcliffe, EL, Bunting, KL, Li, J, Goodall, KJ, Poon, IKA, Hulett, MD, Freeman, C, Zafar, A, McInnes, RL, Taya, T, Parish, CR & 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 (Austin), vol. 3, no. 3, pp. 130-145.

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 L; Bunting, Karen L.; Li, Jasmine; Goodall, Katharine J.; Poon, Ivan K A; Hulett, Mark D.; Freeman, Craig; Zafar, Anjum; McInnes, Russell L.; Taya, Toshiki; Parish, Christopher R; Rao, Sudha.

In: Transcription (Austin), Vol. 3, No. 3, 05.2012, p. 130-145.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - 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.

AU - He, Yi Qing

AU - Sutcliffe, Elissa L

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AU - Li, Jasmine

AU - Goodall, Katharine J.

AU - Poon, Ivan K A

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AU - Freeman, Craig

AU - Zafar, Anjum

AU - McInnes, Russell L.

AU - Taya, Toshiki

AU - Parish, Christopher R

AU - Rao, Sudha

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N2 - 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.

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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KW - Inducible genes

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