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Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory

ABSTRACT: Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at <50 loci, including the homeodomain transcription factor Meis2. Small RNA-mediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion.

ORGANISM(S): Mus musculus

PROVIDER: GSE87675 | GEO | 2016/10/06

SECONDARY ACCESSION(S): PRJNA345538

REPOSITORIES: GEO

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Mus musculus

Project description:Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory

| PRJNA345538 | ENA

A Thalamic Orphan Receptor Drives Variability in Short Term Memory

Project description:Working memory is a form of short-term memory that involves maintaining and updating task relevant information toward goal-directed pursuits. Classical models posit persistent activity in prefrontal cortex (PFC) as a primary neural correlate, but emerging views suggest additional mechanisms may exist. We screened ~200 genetically diverse mice on a working memory task and identified a genetic locus on Chromosome 5 that contributes to a substantial proportion (17%) of the phenotypic variance. Within the locus, we identified a gene encoding an orphan G-protein coupled receptor, Gpr12, which is sufficient to drive substantial and bi-directional changes in working memory. Molecular, cellular, and imaging studies revealed that Gpr12 enables high thalamus-PFC synchrony to support memory maintenance and choice accuracy. These findings identify a novel orphan receptor as a potent modifier of short-term memory, and supplement classical PFC-based models with an emerging thalamus-centric framework for the mechanistic understanding of working memory.

2020-10-01 | GSE156836 | GEO

Single-cell RNA and electrophysiological profiling of D1+ and D2+ principal neurons of the prefrontal cortex

Project description:Dopaminergic modulation of the prefrontal cortex (PFC) circuits is crucial for cognitive processes such as working memory, planning, attention and dysfunction. This system has been linked to cognitive deficits associated with schizophrenia and autism spectrum disorders. Despite its physiological and pathophysiological importance, we are still lacking a clear understanding of the basic principles of dopamine (DA) actions in the PFC. We set out to provide a detailed classification of layer 5 pyramidal neurons mediating the two main streams of DA signaling, namely via DA receptor group 1 (D1) and DA receptor group 2 (D2). To achieve this, we combined electrophysiological whole-cell recordings in acute slices of the prelimbic part (PL) of the medial PFC with single cell RNA sequencing, morphological and immunohistochemical analysis.

2020-07-01 | GSE129125 | GEO

Comparison of gene expression changes following knockdown of KMT2A and MSK1 in mouse embryonic fibroblasts

Project description:The KMT2A/MLL1 lysine methyltransferase complex is an epigenetic regulator of selected developmental genes, in part through the SET-domain-catalyzed methylation of H3K4. It is essential for normal embryonic development and haematopoiesis and frequently mutated in cancer. The catalytic properties and targeting of KMT2A/MLL1 depend on the proteins with which it complexes and the post-translational protein modifications which some of these proteins put in place, though detailed mechanisms remain unclear. We have shown that KMT2A/MLL1 (both native and FLAG-tagged) and Msk1 (RPS6KA5), co-immunoprecipitated in various cell types. This experiment showed that the great majority of genes whose activity changed on KTM2A/MLL1 knockdown responded comparably to Msk1 knockdown.

2016-10-26 | GSE89141 | GEO

Gene expression of L3 and L5 pyramidal neurons in the DLPFC comparing schizophrenia from bipolar major depressive disorders and unaffected subjects.

Project description:Impairments in certain cognitive processes (e.g., working memory) are typically most pronounced in schizophrenia (SZ), intermediate in bipolar disorder (BP) and least in major depressive disorder (MDD). Given that working memory depends, in part, on neural circuitry that includes pyramidal neurons in layer 3 (L3) and layer 5 (L5) of the dorsolateral prefrontal cortex (DLPFC), we sought to determine if transcriptome alterations in these neurons were shared or distinctive for each diagnosis.

2017-04-04 | GSE87610 | GEO

Neuronal Nsun2 deficiency is associated with codon-specific epitranscriptomic dysregulation of Gly-tRNAs and corresponding proteomic shift impacting synaptic signaling and behavior

Project description:The role of transfer (t)RNA cytosine methyl-transferases as epitranscriptomic regulators of brain proteomes remains unexplored. We report that fear memory and antidepressant-like behaviors are highly sensitive to bi-directional changes in Nsun2 tRNA methyltransferase activity in prefrontal cortex (PFC) neurons. Nsun2-deficient mutant cortex showed a selective deficit in multiple glycine tRNAs, resulting in codon-specific shifts in translational efficiencies and a distorted proteomic landscape with deficits in glycine-rich neuronal proteins impacting synaptic signaling and behavior.

2021-07-02 | PXD023437 | Pride

Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers

Project description:Histone lysine-specfic methyltransferase 2 (KMT2A-D) proteins, alternatively called mixed lineage leukaemia (MLL1-4) proteins, mediate positive transcriptional memory. As the catalytic subunits of human COMPASS-like complexes, they methylate H3K4 at promoters and enhancers. KMT2A-D contain understudied highly conserved triplets and a quartet of plant homeodomains (PHDs). Here, we show that all clustered PHDs localise to the well-defined loci of H3K4me3 and H3 acetylation-rich active promoters and enhancers. Surprisingly, we observe little difference in binding pattern between PHDs from promoter-specific KMT2A-B and enhancer-specific KMT2C-D. Fusion of the KMT2A CXXC domain to the PHDs drastically enhances their preference for promoters over enhancers. Hence, the presence of CXXC domains in KMT2A-B, but not KMT2C-D, may explain the promoter/enhancer preferences of the full-length proteins. Importantly, targets of PHDs overlap with KMT2A targets and are enriched in genes involved in the cancer pathways. We also observe that PHDs of KMT2A-D are mutated in cancer, especially within conserved folding motifs (Cys4HisCys2Cys/His), which cause a domain loss-of-function. Taken together, our data suggests that PHDs of KMT2A-D guide the full-length proteins to active promoters and enhancers, and thus play a role in positive transcriptional memory.

2022-12-08 | GSE185921 | GEO

Multi-omics analysis of MEN1 missense mutations identifies disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity

Project description:Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes in the nucleus. We identified three missense mutations, R52G, E255K and E359K, which display predominant reduction in interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions.

2022-10-14 | PXD031928 | Pride

Expression analysis on Mll1+/+ and Mll1-/- MEFs

Project description:Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. The Set1/COMPASS was the founding member and the only H3K4 methylases in S. cerevisiae, however, in mammals at least six H3K4 methylases Set1A/B and MLL1-4 are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation pattern in wild-type Mll1+/+ and Mll1-/- mouse fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, Menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/4 and/or the Set1 complexes have little to no effect on the Hox loci H3K4 methylation or expression levels in these MEFs. Together these data provide insight into redundancy and specialization of COMPASS-like complexes in mammals and provide evidence on a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation. Expression arrays were done with Mll1+/+ and Mll1-/- mouse embryonic fibroblasts. Four replicates were done (dyes were swapped). DNA was hybridized to Agilent Mouse Whole Genome Expression Arrays (4x44k).

2009-10-20 | E-GEOD-18261 | biostudies-arrayexpress

Neuronal Nsun2 deficiency is associated with codon-specific epitranscriptomic dysregulation of Gly-tRNAs and corresponding proteomic shift impacting synaptic signaling and behavior

Project description:Epitranscriptomic mechanisms linking the brain proteome to cognition and complex behaviors essentially remain unexplored. Here, we describe bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of NOL1/NOP2/SUN domain 2 (Nsun2) in the prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a sharp drop in tRNA m5C levels, resulting in significant deficits in expression of 70% (7/10) of tRNAGlyGCC, GlyCCC GlyTCC isodecoders, while expression changes in non-glycinergic tRNAs were minimal (4/152). Altogether, 1488/5820 proteins were sensitive to neuronal Nsun2-deficiency, in conjunction with GCC and CCC codon-specific defects in translational efficiencies and loss of Gly-rich proteins critical for glutamatergic neurotransmission, resulting in impaired synaptic signaling at PFC pyramidal neurons and impairments in contextual fear memory. These distortions in the neuronal translatome were associated with an adaptive, 2.46-fold up-regulation in PFC glycine levels with increased expression of multiple enzymes in the glycine biosynthetic pathway. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC and link synaptic plasticity and complex behaviors to epitranscriptomic regulation of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.

2021-07-01 | GSE165202 | GEO

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