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

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

PROVIDER: PRJNA549701 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9328630.fastq.gz	Fastqsanger.gz
	SRR9328640.fastq.gz	Fastqsanger.gz
	SRR9328650.fastq.gz	Fastqsanger.gz
	SRR9328660.fastq.gz	Fastqsanger.gz
	SRR9328670_1.fastq.gz	Fastqsanger.gz

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

Project description:The acquisition of neuronal identity requires the coordinated action of transcription factors and chromatin-modifying enzymes. However, little is known about the mechanisms that are responsible for maintaining neuronal identity throughout life. The paralogous lysine acetyltransferases CBP and p300 are both essential during development, but their specific function in postmitotic neurons remains unclear. Here, we show that when both KATs are simultaneously knocked out in excitatory neurons of the mouse adult brain, the mice express a rapidly progressing neurological phenotype. This phenotype is associated with a loss of physiological, morphological and transcriptional features defining excitatory neuron identity. This correlates with a dramatic loss of H3K27 acetylation and occupancy by pro-neural transcription factors at neuron-specific genes and enhancers. Restoring CBP expression or lysine acetylation restitutes neuronal-specific gene expression. These experiments demonstrate that CBP and p300 are jointly necessary for maintaining neuronal identity and function by preserving correct chromatin acetylation levels in the adult brain.

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

Project description: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.

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Project description:The transcriptional programs that establish neuronal identity evolved to produce a rich diversity of neuronal cell types that arise sequentially during development. Remarkably, transient expression of certain transcription factors (TFs) can also endow non-neural cells with neuronal properties. To decipher the relationship between reprogramming factors and transcriptional networks that produce neuronal identity and diversity, we screened ~600 TF pairs and identified 76 that produce induced neurons (iNs) from fibroblasts. By intersecting the transcriptomes of iNs with those of endogenous neurons, we define a “core” cell-autonomous neuronal signature. The iNs also exhibit diversity; each TF pair produces iNs with unique transcriptional patterns that can predict their pharmacological responses. By linking distinct TF input “codes” to defined transcriptional outputs, this study uncovers cell autonomous features of neuronal identity and expands the reprogramming toolbox to enable more facile engineering of induced neurons with desired patterns of gene expression and related functional properties.

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Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [ChIP-seq]

Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and directchum regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Genome-wide examination of histone H3 and H4 acetylation, as well as ACSS2 binding, in undifferentiated CAD cells and differentiated CAD neurons; background adjusted by H3 ChIP or Input.

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