Nicholson, Thomas, Su, Hui, Hevi, Sarah, Bajko, Jeff, Wang, Jing, Valdez, Reginald, Loureiro, Joseph, Cheng, Xiaodong, Li, En, Kinzel, Bernd, Labow, Mark and Chen, Taiping (2013) Defective heart development in hypomorphic Lsd1 mice. PLoS One, 8 (4). ISSN 1932-6203

Abstract

Lysine-specific demethylase 1 (Lsd1/Aof2/Kdm1a), the first enzyme with specific lysine demethylase activity to be described, demethylates several target proteins, including histones, DNMT1 and p53. Lsd1 can act as either a transcriptional activator or repressor, depending on the histone lysine it demethylates; its specificity for either H3K4 or H3K9 appears to be determined by its binding partners. We have previously demonstrated that a complete loss of this protein results in early embryonic lethality. However, it was also noted that no adult mice homozygous for the floxed allele survived, even though this allele should be indistinguishable from wild-type Lsd1 after splicing removes the LoxP sites. Homozygous pups die perinatally, with most animals showing major heart development defects. The Aof22lox allele contains two point mutations; the resulting protein shows reduced interaction with known binding partners and decreased enzymatic activity. The expression of a very limited subset of genes is altered in the hearts. This includes an increase in CK2beta expression, the regulatory subunit of the CK2 kinase, which results in E-cadherin hyperphosphorylation. These results identify a previously unknown role for Lsd1 in heart development, through the control of E-cadherin phosphorylation.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/3971