title: Defective heart development in hypomorphic LSD1 mice.
abstract: 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 advance online publication 6 December 2011; doi:10.1038/cr.2011.194.
authors.affiliation: 1] Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA [2] Epigenetics Program, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Nicholson
authors.affiliation: 1] Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA [2] Epigenetics Program, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Su
authors.affiliation: 1] Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA [2] Epigenetics Program, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hevi
authors.affiliation: Epigenetics Program, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Epigenetics Program, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Bajko
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Reginald
authors.initials: R
authors.lastname: Valdez
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Loureiro
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Epigenetics Program, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Novartis Pharma AG Forum 1 Novartis Campus CH-4056, Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Labow
authors.affiliation: 1] Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA [2] Epigenetics Program, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA [3] Current address: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen