Sequence-specific recruitment of heterochromatin protein 1 via interaction with Krüppel-like factor 11, a human transcription factor involved in tumor suppression and metabolic diseases

Gwen Lomberk, Angela J. Mathison, Adrienne Grzenda, Seungmae Seo, Cathrine J. DeMars, Sumera Rizvi, Juliana Bonilla-Velez, Ezequiel Calvo, Martin E Fernandez-Zapico, Juan Iovanna, Navtej Singh Buttar, Raul Urrutia

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Heterochromatin protein 1 (HP1) proteins are "gatekeepers"of epigenetic gene silencing that is mediated by lysine 9 of histone H3 methylation (H3K9me). Current knowledge supports a paradigm whereby HP1 proteins achieve repression by binding to H3K9me marks and interacting to H3K9 histone methyltransferases (HMTs), such as SUV39H1, which methylate this residue on adjacent nucleosomes thereby compacting chromatin and silencing gene expression. However, the mechanism underlying the recruitment of this epigenetic regulator to target gene promoters remains poorly characterized. In the current study, we reveal for the first time a mechanism whereby HP1 is recruited to promoters by a well characterized Krüppel-like transcription factor (KLF), in a sequence-specific manner, to mediate complex biological phenomena. A PXVXL HP1-interacting domain identified at position 487-491 of KLF11 mediates the binding of HP1α and KLF11 in vitro and in cultured cells. KLF11 also recruits HP1α and its histone methyltransferase, SUV39H1, to promoters to limit KLF11-mediated gene activation. Indeed, a KLF11ΔHP1 mutant derepresses KLF11-regulated cancer genes, by inhibiting HP1-SUV39H1 recruitment, decreasing H3K9me3, while increasing activation-associated marks. Biologically, impairment of KLF11-mediated HP1-HMT recruitment abolishes tumor suppression, providing direct evidence that HP1-HMTs act in a sequence-specific manner to achieve this function rather than its well characterized binding to methylated chromatin without intermediary. Collectively, these studies reveal a novel role for HP1 as a cofactor in tumor suppression, expand our mechanistic understanding of a KLF associated to human disease, and outline cellular and biochemical mechanisms underlying this phenomenon, increasing the specificity of targeting HP1-HMT complexes to gene promoters.

Original languageEnglish (US)
Pages (from-to)13026-13039
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number16
DOIs
StatePublished - Apr 13 2012

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Metabolic Diseases
Tumors
Transcription Factors
Neoplasms
Genes
Epigenomics
Chromatin
heterochromatin-specific nonhistone chromosomal protein HP-1
Chemical activation
Biological Phenomena
Methylation
Nucleosomes
Neoplasm Genes
Gene Silencing
Gene expression
Histones
Transcriptional Activation
Lysine
Cultured Cells
Carrier Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Sequence-specific recruitment of heterochromatin protein 1 via interaction with Krüppel-like factor 11, a human transcription factor involved in tumor suppression and metabolic diseases. / Lomberk, Gwen; Mathison, Angela J.; Grzenda, Adrienne; Seo, Seungmae; DeMars, Cathrine J.; Rizvi, Sumera; Bonilla-Velez, Juliana; Calvo, Ezequiel; Fernandez-Zapico, Martin E; Iovanna, Juan; Buttar, Navtej Singh; Urrutia, Raul.

In: Journal of Biological Chemistry, Vol. 287, No. 16, 13.04.2012, p. 13026-13039.

Research output: Contribution to journalArticle

Lomberk, Gwen ; Mathison, Angela J. ; Grzenda, Adrienne ; Seo, Seungmae ; DeMars, Cathrine J. ; Rizvi, Sumera ; Bonilla-Velez, Juliana ; Calvo, Ezequiel ; Fernandez-Zapico, Martin E ; Iovanna, Juan ; Buttar, Navtej Singh ; Urrutia, Raul. / Sequence-specific recruitment of heterochromatin protein 1 via interaction with Krüppel-like factor 11, a human transcription factor involved in tumor suppression and metabolic diseases. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 16. pp. 13026-13039.
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abstract = "Heterochromatin protein 1 (HP1) proteins are {"}gatekeepers{"}of epigenetic gene silencing that is mediated by lysine 9 of histone H3 methylation (H3K9me). Current knowledge supports a paradigm whereby HP1 proteins achieve repression by binding to H3K9me marks and interacting to H3K9 histone methyltransferases (HMTs), such as SUV39H1, which methylate this residue on adjacent nucleosomes thereby compacting chromatin and silencing gene expression. However, the mechanism underlying the recruitment of this epigenetic regulator to target gene promoters remains poorly characterized. In the current study, we reveal for the first time a mechanism whereby HP1 is recruited to promoters by a well characterized Kr{\"u}ppel-like transcription factor (KLF), in a sequence-specific manner, to mediate complex biological phenomena. A PXVXL HP1-interacting domain identified at position 487-491 of KLF11 mediates the binding of HP1α and KLF11 in vitro and in cultured cells. KLF11 also recruits HP1α and its histone methyltransferase, SUV39H1, to promoters to limit KLF11-mediated gene activation. Indeed, a KLF11ΔHP1 mutant derepresses KLF11-regulated cancer genes, by inhibiting HP1-SUV39H1 recruitment, decreasing H3K9me3, while increasing activation-associated marks. Biologically, impairment of KLF11-mediated HP1-HMT recruitment abolishes tumor suppression, providing direct evidence that HP1-HMTs act in a sequence-specific manner to achieve this function rather than its well characterized binding to methylated chromatin without intermediary. Collectively, these studies reveal a novel role for HP1 as a cofactor in tumor suppression, expand our mechanistic understanding of a KLF associated to human disease, and outline cellular and biochemical mechanisms underlying this phenomenon, increasing the specificity of targeting HP1-HMT complexes to gene promoters.",
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AU - Seo, Seungmae

AU - DeMars, Cathrine J.

AU - Rizvi, Sumera

AU - Bonilla-Velez, Juliana

AU - Calvo, Ezequiel

AU - Fernandez-Zapico, Martin E

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