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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. J Biol Chem 2012 Apr 13;287(16):13026-39 PMID: 22318730 PMCID: PMC3339955

Pubmed ID

22318730

DOI

10.1074/jbc.M112.342634

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.

Author List

Lomberk G, Mathison AJ, Grzenda A, Seo S, DeMars CJ, Rizvi S, Bonilla-Velez J, Calvo E, Fernandez-Zapico ME, Iovanna J, Buttar NS, Urrutia R

Authors

Gwen Lomberk PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-84859753082   35 Citations

MESH terms used to index this publication - Major topics in bold

Animals
CHO Cells
Cell Cycle Proteins
Cell Death
Cell Division
Cell Line, Tumor
Cellular Senescence
Chromatin
Chromosomal Proteins, Non-Histone
Cricetinae
Female
Gene Expression Regulation, Neoplastic
Genes, Tumor Suppressor
Humans
Metabolic Diseases
Mice
Mice, Nude
Neoplasm Transplantation
Neoplasms
Promoter Regions, Genetic
Receptors, CXCR4
Repressor Proteins
Transcription, Genetic
Transplantation, Heterologous
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad