A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner

Abstract

Histone modifications have a profound impact on the chromatin structure and gene expression and their correct establishment and recognition is essential for correct cell functioning. Malfunction of histone modifying proteins is associated with developmental defects and diseases and detailed characterization of these proteins is therefore very important. The lysine specific demethylase KDM2A is a CpG island binding protein that has been studied predominantly for its ability to regulate CpG island-associated gene promoters by demethylating their H3K36me2. However, very little attention has been paid to the alternative KDM2A isoform that lacks the N-terminal demethylation domain, KDM2A-SF. Here we characterized KDM2A-SF more in detail and we found that, unlike the canonical full length KDM2A-LF isoform, KDM2A-SF forms distinct nuclear heterochromatic bodies in an HP1a dependent manner. Our chromatin immunoprecipitation experiments further showed that KDM2A binds to transcriptionally silent pericentromeric regions that exhibit high levels of H3K36me2. H3K36me2 is the substrate of the KDM2A demethylation activity and the high levels of this histone modification in the KDM2A-bound pericentromeric regions imply that these regions are occupied by the demethylation deficient KDM2A-SF isoform.

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

“…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). Similarly, the fact that the KDM2B-SF specific knockout phenotype is different from that of the KDM2B-LF loss-of-function mutants also implies different functions for the short and long isoforms (25)(26)(27)).…”

“…Although KDM2A and KDM2B have very similar 3 structure, they have been shown to interact with different protein partners to repress different target regions. For example, KDM2A interacts with HP1a to repress the pericentromeric heterochromatin (11)(12)(13), whereas KDM2B forms complex with the PRC1 complex to silence developmentally important genes in embryonic stem cells (10).…”

Lysine-specific demethylase 2A gene expression in clear cell renal cell carcinoma and its clinical significance

“…Through the methylation of different histone sites, gene expressions can be regulated by influencing the activation and inhibition of transcription [5]. The constant level of covalent histone methylation is under the control of histone methyltransferases and demethylases [6]. The lysine-specific demethylase 2A gene (KDM2A), found on chromosome 11q13.2, is a member of the KDM histone lysine demethylase family, which exhibits specificity for removal of methyl groups of histone H3K36 by binding directly to CpG islands in gene promoters [6].…”

“…The constant level of covalent histone methylation is under the control of histone methyltransferases and demethylases [6]. The lysine-specific demethylase 2A gene (KDM2A), found on chromosome 11q13.2, is a member of the KDM histone lysine demethylase family, which exhibits specificity for removal of methyl groups of histone H3K36 by binding directly to CpG islands in gene promoters [6]. The dysfunction of KDM2A has been reported in various cancers, and its loss-of-function mouse mutants are embryonically lethal [6].…”

“…The lysine-specific demethylase 2A gene (KDM2A), found on chromosome 11q13.2, is a member of the KDM histone lysine demethylase family, which exhibits specificity for removal of methyl groups of histone H3K36 by binding directly to CpG islands in gene promoters [6]. The dysfunction of KDM2A has been reported in various cancers, and its loss-of-function mouse mutants are embryonically lethal [6]. However, KDM2A has a complex and tissue-specific role in tumorigenesis and tumor progression.…”