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Defective heart development in hypomorphic LSD1 mice

Thomas B Nicholson1,2, Hui Su1,2, Sarah Hevi1,2, Jing Wang2, Jeff Bajko2, Mei Li1, Reginald Valdez1, Joseph Loureiro1, Xiaodong Cheng3, En Li2, Bernd Kinzel4, Mark Labow1 and Taiping Chen1,2,5

1Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
2Epigenetics Program, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
3Department of Biochemistry, Emory University, Atlanta, GA 30322, USA
4Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Novartis Pharma AG Forum 1 Novartis Campus CH-4056, Basel, Switzerland
5Current address: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
* Correspondence: Taiping Chen, Tel: +1-512-237-9479; Fax: +1-512-237-2475

Lysine-specific demethylase 1 (LSD1/AOF2/KDM1A), the first enzyme with specific lysine demethylase activity to be described, demethylates histone and non-histone proteins and is essential for mouse embryogenesis. LSD1 interacts with numerous proteins through several different domains, most notably the tower domain, an extended helical structure that protrudes from the core of the protein. While there is evidence that LSD1-interacting proteins regulate the activity and specificity of LSD1, the significance and roles of such interactions in developmental processes remain largely unknown. Here we describe a hypomorphic LSD1 allele that contains two point mutations in the tower domain, resulting in a protein with reduced interaction with known binding partners and decreased enzymatic activity. Mice homozygous for this allele die perinatally due to heart defects, with the majority of animals suffering from ventricular septal defects. Transcriptional profiling revealed altered expression of a limited subset of genes in the hearts. This includes an increase in calmodulin kinase (CK) 2β, the regulatory subunit of the CK2 kinase, which correlates with E-cadherin hyperphosphorylation. These results identify a previously unknown role for LSD1 in heart development, perhaps partly through the control of E-cadherin phosphorylation.

Cell Research (2013) 23:10-12. doi:10.1038/cr.2012.112; published online 31 July 2012

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