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Human Molecular Genetics Advance Access published online on October 26, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl423
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received July 14, 2006
Revised October 23, 2006
Accepted October 23, 2006

Article

Lmo7 is an emerin-binding protein that regulates the transcription of emerin and many other muscle-relevant genes

James M. Holaska 1, Soroush Rais-Bahrami 1, and Katherine L. Wilson 1 *

1 Department of Cell Biology The Johns Hopkins University School of Medicine 725 N. Wolfe Street Baltimore, MD 21205

* To whom correspondence should be addressed.
Katherine L. Wilson, E-mail: klwilson{at}jhmi.edu


  Abstract

X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is inherited through mutations in emerin, a nuclear membrane protein. Emerin has proposed roles in nuclear architecture and gene regulation, but direct molecular links to disease were unknown. We report that Lim-domain only 7 (Lmo7) binds emerin directly with 125 nM affinity; the C-terminal half of human Lmo7 (hLmo7C) was sufficient to bind emerin in vitro. Lmo7 appeared relevant to EDMD because a deletion that removes Lmo7 (plus eight exons of a neighboring gene) in mice causes dystrophic muscles (1). Lmo7 localizes in the nucleus, cytoplasm and cell surface, particularly adhesion junctions (2). Our data suggest endogenous Lmo7 is a nucleocytoplasmic shuttling protein, and might also localize at focal adhesions in HeLa cells. Two key results show that Lmo7 regulates emerin gene expression: rat Lmo7 isoforms directly activated a luciferase reporter gene in vivo, and emerin mRNA expression decreased 93% in Lmo7-downregulated HeLa cells. Thus, Lmo7 not only binds emerin protein but is also required for emerin gene transcription. Microarray analysis of Lmo7-downregulated HeLa cells identified over 4200 misregulated genes, including 46 genes important for muscle or heart. Misregulation of 11 genes, including four (CREBBP, NAP1L1, LAP2, RBL2) known to be misregulated in X-EDMD patients and emerin-null mice (3, 4) was confirmed by real-time PCR. Overexpression of wildtype emerin, but not emerin mutant P183H (which causes EDMD and selectively disrupts binding to Lmo7), decreased the expression of CREBBP, NAP1L1 and LAP2, suggesting Lmo7 activity is both EDMD-relevant and inhibited by direct binding to emerin. We conclude that Lmo7 positively regulates many EDMD-relevant genes (including emerin), and is feedback-regulated by binding to emerin.


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