title: 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.
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.
authors: Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
authors: Yi Qing
authors: YQ
authors: He
authors: Elissa L
authors: EL
authors: Sutcliffe
authors: Karen L
authors: KL
authors: Bunting
authors: Jasmine
authors: J
authors: Li
authors: Katharine J
authors: KJ
authors: Goodall
authors: Ivan K A
authors: IK
authors: Poon
authors: Mark D
authors: MD
authors: Hulett
authors: Craig
authors: C
authors: Freeman
authors: Anjum
authors: A
authors: Zafar
authors: Russell L
authors: RL
authors: McInnes
authors: Toshiki
authors: T
authors: Taya
authors: Christopher R
authors: CR
authors: Parish
authors: Sudha
authors: S
authors: Rao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005455:Fluorescent Antibody Technique; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism*; D015533:Transcriptional Activation; D000099175:Heparanase
chemical_list: D002843:Chromatin; D005966:Glucuronidase; D056466:Histone Demethylases; D006657:Histones; D034741:RNA, Small Interfering; D000099175:Heparanase