KDM2A/B lysine demethylases and their alternative isoforms in development and disease

Abstract

Aberrant levels of histone modifications lead to chromatin malfunctioning and consequently to various developmental defects and human diseases. Therefore, the proteins bearing the ability to modify histones have been extensively studied and the molecular mechanisms of their action are now fairly well understood. However, little attention has been paid to naturally occurring alternative isoforms of chromatin modifying proteins and to their biological roles. In this review, we focus on mammalian KDM2A and KDM2B, the only two lysine demethylases whose genes have been described to produce also an alternative isoform lacking the N-terminal demethylase domain. These short KDM2A/B-SF isoforms arise through alternative promoter usage and seem to play important roles in development and disease. We hypothesise about the biological significance of these alternative isoforms, which might represent a more common evolutionarily conserved regulatory mechanism.

Alternative isoforms of KDM2A and KDM2B lysine demethylases negatively regulate canonical Wnt signaling

“…Therefore, KDM2A/B-SF are not able to demethylate the KDM2A/B target lysines, but they still have the ability to bind to the same DNA regions as KDM2A/B-LF and to interact with the same proteins as KDM2A/B-LF. KDM2A/B-SF are thus likely to compete with KDM2A/B-LF or to complement their function (1). Despite the fact that a KDM2A-SF specific knockout mutant has not been described yet and it cannot be compared to the embryonically lethal KDM2A-LF knockout phenotype (24), we previously showed that the distinct KDM2A positive nuclear structures on pericentromeric heterochromatin are formed by KDM2A-SF and not by KDM2A-LF (12).…”

“…KDM2B is able to demethylate also H3K4me3 (3). By demethylating H3K36me1/2 and H3K4me3 in transcriptionally active promoters (4)(5)(6), KDM2A/B function as transcriptional repressors of the promoters that contain CpG islands (1,(7)(8)(9)(10). Although KDM2A and KDM2B have very similar 3 structure, they have been shown to interact with different protein partners to repress different target regions.…”

Alternative isoforms of KDM2A and KDM2B lysine demethylases negatively regulate canonical Wnt signaling

“…KDM2A and KDM2B (KDM2A/B) are two closely related lysine demethylases with the ability to bind to non-methylated CpG islands through their CXXC DNA binding domain. After binding to non-methylated CpG islands in transcriptionally active promoters, KDM2A/B demethylate mono- and di-methylated H3K36 lysines (H3K36me1/2) using their N-terminal Jumonji-C demethylase domain [ 1 , 2 ]. KDM2B is able to demethylate also H3K4me3 [ 3 ].…”

“…KDM2B is able to demethylate also H3K4me3 [ 3 ]. By demethylating H3K36me1/2 and H3K4me3 in transcriptionally active promoters [ 4 – 6 ], KDM2A/B function as transcriptional repressors of the promoters that contain CpG islands [ 1 , 7 – 10 ]. Although KDM2A and KDM2B have very similar structure, they have been shown to interact with different protein partners to repress different target regions.…”

Nuevas funciones de la quinasa humana VRK1 en la respuesta al daño en el ADN y la estructura de la cromatina

“…Los modificadores de cromatina más importantes que median esta trimetilación pertenecen a la familia MLL y a los complejos SETD1 y 2 (40,270), mientras que son varias las demetilasas (KDMs) que se encargan de la eliminación del grupo metilo de este residuo. Una de ellas es KDM2B, capaz de demetilar esta lisina de la histona H3 junto con otras dos marcas epigenéticas (H3K36me1/2 y H3K79me2/3) en los promotores transcripcionalmente activos (271). Las demás pertenecen a la subfamila KDM5 y se caracterizan por la presencia de un dominio catalítico JmjC y por demetilar también a la H3K4me2 (272).…”