A Hypomorphic Lsd1 Allele Results in Heart Development Defects in 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. Molecular analyses revealed hyperphosphorylation of E-cadherin in the hearts of mutant animals. These results identify a previously unknown role for Lsd1 in heart development, perhaps partly through the control of E-cadherin phosphorylation.

Epigenetic mechanisms in heart development and disease

“…Members of the histone demethylase Jumonji family have been implicated in septation, because their deletion results in ventricular septal defects and outflow tract defects [66–68]. In addition, other lysine demethylases such as LSD-1 have also been shown to cause ventricular septal defects [69,70]. Together, these findings illustrate the pervasive roles of histone modifications in heart development.…”

Epigenetic Molecular Recognition: A Biomolecular Modeling Perspective

“…JmjC demethylase belongs to a family of Fe 2 + -dependent dioxygenases, which is broader than the FADdependent demethylases and use Fe 2 + and a-ketoglutarate as cofactors. [53][54][55] Epigenetic drugs-acting on DNA accessibility rather than modification itself-hold great promise relative to the toxicity observed in the traditional treatment of these diseases using chemotherapy. [49,50] JmjC demethylases are also more versatile in terms of their substrate specificity relative to FAD-dependent demethylases.…”

“…[47,62,64] Mutations in the SANT2 domain decrease enzymatic activity in the presence of nucleosomes, indicating the role of the SANT2 domain for interactions with chromatin. [55] [55] …”

“…[51,52] Recently, the role of LSD1 in neurological disorders, organ development, and viral infections has also been proposed. [53][54][55] Epigenetic drugs-acting on DNA accessibility rather than modification itself-hold great promise relative to the toxicity observed in the traditional treatment of these diseases using chemotherapy. [56] Therefore, supported by evidence that LSD1 is a binding partner of HDAC1/2 (see above) and other bromodomain-containing proteins, [57] LSD1 is a particularly attractive target for epigenetic drug discovery and design, not limited to anticancer drugs.…”

“…[59] Recent studies with mouse models show that two single point mutations in the CoREST Tower domain (Glu413Gly and Met448Val) decrease the association strength of CoREST with LSD1, resulting in defective heart development in mammals. [55]…”