KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions

Abstract

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases.

Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease

“…Isolated nuclei (prepared as in the ChIP-seq protocol) were stained with an anti-NeuN antibody (Millipore # MAB 377× 60 ; Alexa Fluor-488 conjugated) in presence of 5% goat serum and incubated in the dark for 1 h. NeuN-stained nuclei were analyzed on a BD LSR II flow cytometer (at the UPenn FACS core facility) with gates set according to nuclei size, NeuN intensity and an IgG control.…”

Characterization ofSETD1Ahaploinsufficiency in humans andDrosophiladefines a novel neurodevelopmental syndrome

“…It is notable that in humans all six H3K4 methyltransferases, SETD1A/B, KMT2A/B, and KMT2C/D have been implicated in neurodevelopmental disorders, though it is also clear that all KMT2 members have distinct molecular functions 30,41,[49][50][51] . However, there is an interesting overlap between these chromatin modulating genes and their respective phenotypes (with developmental delay/intellectual disability at its core), based on their shared underlying disease mechanisms 52 .…”

Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

“…Hence, DNA methylation can directly regulate CREB‐dependent gene expression. This could affect CREB target genes, such as c‐fos , indicating that methylation might be a common way to regulate learning genes …”

“…Recent studies show that molecular processes involved in LTM consolidation and plasticity involve additional gene regulatory mechanisms. Epigenetic mechanisms such as DNA methylation and histone acetylation as well as the role of cofactors are gaining importance. Moreover, recent evidence suggests that CREB initiates a gene regulatory cascade, which appears to be critical for long‐lasting memories .…”