K‐Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation

Abstract

Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone-modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K-acetyltransferase 2a (Kat2a)-a HAT that has not been studied for its role in memory function so far-shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long-term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa-light-chainenhancer of activated B cells (NF-jB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation.

Satb2 determines miRNA expression and long-term memory in the adult central nervous system

“…We detected the expression of 476 miRNAs in the CA1 tissue, similar to the number reported for this hippocampal subfield in a previous study (Stilling et al, 2014). Of these 464 miRNAs 43.9% showed significant differential expression between Satb2 cKO and control mice (Figure 6A, Figure 6—source data 3).…”

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

“…Both aging and amyloid deposition were associated with a transcriptional program predominately linked to inflammation, which is in line with previous findings (80)(81)(82)(83). Since aging is not associated with massive changes in the number of glial cells (37,84), our data indicate that the gene-expression program linked to inflammation reflects activity changes. Given that the same pathways were affected in APP/PS1-21 mice, albeit much more strongly, our data suggest that, also in response to amyloid pathology, inflammation is initially mediated by changes in cell activity, but later also dominated by increased cell number.…”

“…Our data, however, also show that SAHA could partially reinstate physiological expression of aging-upregulated genes that were linked to inflammation (Figure 1, I and J, and Supplemental Figure 2). Since this effect cannot easily be explained by changes in histone acetylation, we speculate that processes related to the acetylation of nonhistone proteins, such as transcription factors, might be involved (37)(38)(39). To address this issue, we first examined transcription factor-binding sites linked to aging-upregulated genes.…”

HDAC1 links early life stress to schizophrenia-like phenotypes

“…The following antibodies were commercially purchased and used at the cited concentrations: GAPDH (1:5,000; Chemicon), HDAC1 (1:1,000; Diagenode), GFP, Cy3-labeled (goat anti-rabbit, 1:500; Jackson ImmunoResearch), and Alexa 488-labeled (donkey anti-mouse, 1:500; Invitrogen). Immunostaining was performed as described previously (57,62) and analyzed using a Leica SP2 confocal microscope. The following antibodies were commercially purchased and used at the cited concentrations: HDAC1 (1:1,000, H-51; Santa Cruz Biotechnology) and Pvalb (1:1,000; Swant).…”