KAT3-dependent acetylation of cell type-specific genes maintains neuronal identity in the adult mouse brain

Abstract

The lysine acetyltransferases type 3 (KAT3) family members CBP and p300 are important transcriptional co-activators, but their specific functions in adult post-mitotic neurons remain unclear. Here, we show that the combined elimination of both proteins in forebrain excitatory neurons of adult mice resulted in a rapidly progressing neurological phenotype associated with severe ataxia, dendritic retraction and reduced electrical activity. At the molecular level, we observed the downregulation of neuronal genes, as well as decreased H3K27 acetylation and pro-neural transcription factor binding at the promoters and enhancers of canonical neuronal genes. The combined deletion of CBP and p300 in hippocampal neurons resulted in the rapid loss of neuronal molecular identity without de-or transdifferentiation. Restoring CBP expression or lysine acetylation rescued neuronal-specific transcription in cultured neurons. Together, these experiments show that KAT3 proteins maintain the excitatory neuron identity through the regulation of histone acetylation at cell type-specific promoter and enhancer regions.

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders

“…The same is true for EP300 , which is located on chromosome 22q13.2; both with regards to chromosome aberrations and coding sequence mutations (Korzus, 2017 ). CBP and p300 target numerous lysine residues on all four histones: H2A (K5), H2B (K5, K12, K15, K20), H3 (K14, K18, K27), and H4 (K8, K12) (Bedford and Brindle, 2012 ; Valor et al, 2013 ; Lipinski et al, 2020 ). CBP and p300 are critical in many nuclear processes, due both to their respective HAT activities, and their ability to interact with over 400 transcription factors that effectively compete for the proportionally limited amount of CBP/p300 present in the cell (Dyson and Wright, 2016 ).…”

“…Conditional knockouts have also been generated using Cre-loxP systems that target specific regions of the hippocampal formations, such as the dentate gyrus and CA1 using the CamKIIα promoter (Barco, 2007 ; Barrett et al, 2011 ; Lopez-Atalaya et al, 2014 ). CaMKIIα-Cre/ Crebbp mice display impaired short- and long-term memory, and acetylation deficiencies at H2BK12, H3K14, H3K27, and H4K8 (Barrett et al, 2011 ; Lipinski et al, 2020 ). A tetracycline-induced transgenic mouse was developed to allow for temporal control of Crebbp expression (Barco, 2007 ; Lopez-Atalaya et al, 2014 ).…”

Identification of a transcriptional signature found in multiple models of ASD and related disorders

“…Crebbp was one of 5 chromatin modifiers used to generate the transcriptional signatures here and thus we would hypothesize that these signatures would be present in this model if they are relevant to an in vivo system. We used RNA-seq of cortical tissue from a mouse model containing a double knockout of the Kat3a genes (Crebbp and p300) (Lipinski et al, 2020) and examined the direct overlap of differentially expressed genes to the transcriptional signatures. We found a highly significant overlap between genes downregulated in the Rubenstein-Taybi mouse model and the downregulated transcriptional signature (69 genes overlap, p = 1x10 -6 ) (Fig.…”

p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2

“…This includes both activating cell-type-specific genes as well as suppressing nonneuronal and cell cycle-related genes. Dysregulation of gene networks can lead to defects in innervation ( Lin et al., 1998 ; Arber et al., 2000 ; Kania and Jessell., 2003 ; Chen et al., 2013 ), dendritic and axonal deterioration ( Kadkhodaei et al., 2013 ; Lipinski et al., 2020 ), loss of cell-type identity ( Liu et al., 2010 ; Bovetti et al., 2013 ; Montana et al., 2013 ), neuronal network dysfunction ( Chen et al., 2013 ; Kadkhodaei et al., 2013 ; Lipinski et al., 2020 ) and cell death ( Ninkovic et al., 2010 ; von Schimmelmann et al., 2016 ). Thus, it is not surprising that disrupted gene regulation is associated with memory impairment ( Barrett et al., 2011 ; Vogel-Ciernia et al., 2013 ), cognitive dysfunction, and neurodegenerative diseases ( De Jager et al., 2014 ; Sanchez-Mut et al., 2016 ; Watson et al., 2016 ; Berson et al., 2018 ; Li et al., 2019 ).…”