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.
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.
Department of Biochemistry and Molecular Biology, Laboratory of Epigenetics and Chromatin Dynamics, GIH Division, Mayo Clinic, Rochester, Minnesota 55905, USA. lomberk.gwen@mayo.edu
Gwen
G
Lomberk
Angela J
AJ
Mathison
Adrienne
A
Grzenda
Seungmae
S
Seo
Cathrine J
CJ
DeMars
Sumera I
SI
Ilyas
Juliana
J
Bonilla-Velez
Ezequiel
E
Calvo
Martin E
ME
Fernandez-Zapico
Juan
J
Iovanna
Navtej S
NS
Buttar
Raul
R
Urrutia
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016466:CHO Cells; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology; D002843:Chromatin / Q000502:physiology; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D006224:Cricetinae; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D008659:Metabolic Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000502:physiology; D019718:Receptors, CXCR4 / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D014183:Transplantation, Heterologous
D051017:Apoptosis Regulatory Proteins; C000715594:CBX5 protein, human; C527276:CXCR4 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C115117:KLF11 protein, human; D019718:Receptors, CXCR4; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5