The Krüppel-like factor 15 as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy.

Abstract

Facioscapulohumeral muscular dystrophy (FSHD), a dominant hereditary disease with a prevalence of 7 per 100,000 individuals, is associated with a partial deletion in the subtelomeric D4Z4 repeat array on chromosome 4q. The D4Z4 repeat contains a strong transcriptional enhancer that activates promoters of several FSHD-related genes. We report here that the enhancer within the D4Z4 repeat binds the Krüppel-like factor KLF15. KLF15 was found to be up-regulated during myogenic differentiation induced by serum starvation or by overexpression of the myogenic differentiation factor MYOD. When overexpressed, KLF15 activated the D4Z4 enhancer and led to overexpression of DUX4c (Double homeobox 4, centromeric) and FRG2 (FSHD region gene 2) genes, whereas its silencing caused inactivation of the D4Z4 enhancer. In immortalized human myoblasts, the D4Z4 enhancer was activated by the myogenic factor MYOD, an effect that was abolished upon KLF15 silencing or when the KLF15-binding sites within the D4Z4 enhancer were mutated, indicating that the myogenesis-related activation of the D4Z4 enhancer was mediated by KLF15. KLF15 and several myogenesis-related factors were found to be expressed at higher levels in myoblasts, myotubes, and muscle biopsies from FSHD patients than in healthy controls. We propose that KLF15 serves as a molecular link between myogenic factors and the activity of the D4Z4 enhancer, and it thus contributes to the overexpression of the DUX4c and FRG2 genes during normal myogenic differentiation and in FSHD.

• Authors: Petr Dmitriev, Andrei Petrov, Eugenie Ansseau, Luiza Stankevicins, Sébastien Charron, Elena Kim, Tomas Jan Bos, Thomas Robert, Ahmed Turki, Frédérique Coppée, Alexandra Belayew, Vladimir Lazar, Gilles Carnac, Dalila Laoudj, Marc Lipinski, Yegor S Vassetzky
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 52 Pg. 44620-31 (Dec 30 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21937448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• FRG2 protein, human
• KLF15 protein, human
• Klf15 protein, mouse
• Kruppel-Like Transcription Factors
• MyoD Protein
• MyoD1 myogenic differentiation protein
• Nuclear Proteins
• Transcription Factors

Topics

• Animals
• Chromosomes, Human, Pair 4 (genetics, metabolism)
• Cricetinae
• DNA-Binding Proteins (genetics, metabolism)
• Enhancer Elements, Genetic
• Gene Expression Regulation (genetics)
• HeLa Cells
• Humans
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Mice
• Muscle Development (genetics)
• Muscle, Skeletal (metabolism, pathology)
• Muscular Dystrophy, Facioscapulohumeral (genetics, metabolism, pathology)
• MyoD Protein (genetics, metabolism)
• Nuclear Proteins (biosynthesis, genetics, metabolism)
• Transcription Factors (genetics, metabolism)