Biology subjects

Kaas, G. A.

Publications and source records attributed to Kaas, G. A..

5 recordsLinked to original sources

bioRxiv2024

HEXIM1 is correlated with Alzheimer's disease pathology and regulates immediate early gene dynamics in neurons

Cognitive processes require de novo gene transcription in neurons. Memory requires the rapid and robust transcription of a class of genes called immediate early genes (IEGs). IEG transcription is facilitated by the formation of a poised basal state, in which RNA polymerase II (RNAP2) initiates transcription, but remains paused downstream of the promoter. Upon neuronal depolarization, the paused RNAP2 is released to complete the synthesis of messenger RNA (mRNA) transcripts, a process stimulated by positive transcription elongation factor b (P-TEFb). In many cell types, P-TEFb is sequestered into a large inactive complex containing Hexamethylene bisacetamide inducible 1 (HEXIM1), but the impact of this interaction on neuronal gene transcription is not yet fully understood. In this study, we found that neuronal expression levels of HEXIM1 mRNA are highly correlated with impaired cognition in Alzheimers disease. It is also induced in the hippocampus during memory formation, and following depolarization in neurons. The role of HEXIM1 in neuronal gene transcription was then explored in murine neuronal cultures where we found that calcium frees P-TEFb from the HEXIM1 inhibitory complex. Modulation of P-TEFb by inhibiting the activity of the cyclin-dependent kinase 9 (CDK9) subunit of this complex significantly impacts IEG induction, particularly during repeated depolarization. Our findings indicate that HEXIM1 in complex with P-TEFb plays an important role in establishing and resetting the poised RNAP2 state, enabling efficient activation of genes necessary for synaptic plasticity.

neuroscience↗

bioRxiv2024

The oncometabolite D-2-hydroxyglutarate promotes DNA hypermethylation at lineage-specific enhancers controlling microglial activation in IDHmut gliomas

Tumor-associated microglia and macrophages (TAMs), the most abundant myeloid populations in gliomas, shape immune responses through transcriptional programs influenced by the tumor microenvironment. Although these programs differ according to tumor IDH status, the underlying epigenetic mechanisms remain poorly understood. Here, we uncover widespread DNA hypermethylation in the myeloid compartment of IDH-mutant gliomas, predominantly at distal enhancers enriched for motifs of core microglial transcription factors (TFs). This remodeled enhancer landscape strongly correlated with reduced activity of TF regulons and coordinated repression of immunomodulatory programs that normally support microglial activation. Using primary human microglia, we show that prolonged exposure to the oncometabolite D-2-hydroxyglutarate (D-2HG) reduces TET activity and increases 5mC/5hmC ratios near TF-binding motifs within enhancers affected ex vivo. Consistent with these epigenetic alterations, D-2HG-treated microglia exhibited transcriptional signatures compatible with blunted proinflammatory responses, whereas pharmacological inhibition of mutant IDH in patients partially restored microglial immune reactivity. Altogether, our findings reveal a chronic D-2HG-driven epigenetic priming mechanism that promotes a hyporesponsive microglial state, providing a rationale for the immunologically cold phenotype of IDH-mutant gliomas and offering insight into how IDH-targeted therapies may reshape microglial immune responses.

cancer biology↗

bioRxiv2020

Tet1 isoforms differentially regulate gene expression, synaptic transmission and memory in the mammalian brain.

The dynamic regulation of DNA methylation in post-mitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the Tet1 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (Tet1S) encoding an N-terminally truncated TET1 protein and a full-length Tet1 (Tet1FL) transcript encoding canonical TET1 are co-expressed in the adult brain. We show that Tet1S is the predominantly expressed isoform, and is highly enriched in neurons, whereas Tet1FL is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell-type specific. Using viral-mediated, isoform- and neuron-specific molecular tools, we find that Tet1S repression enhances, while Tet1FL impairs, hippocampal-dependent memory. In addition, the individual disruption of the two isoforms leads to contrasting changes in basal synaptic transmission and the dysregulation of unique gene ensembles in hippocampal neurons. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the mammalian brain.

neuroscience↗

bioRxiv2020

Reduced function of the glutathione S-transferase S1 suppresses behavioral hyperexcitability in Drosophila expressing a mutant voltage-gated sodium channel

Voltage-gated sodium (Nav) channels play a central role in the generation and propagation of action potentials in excitable cells such as neurons and muscles. To determine how the phenotypes of Nav-channel mutants are affected by other genes, we performed a forward genetic screen for dominant modifiers of the seizure-prone, gain-of-function Drosophila melanogaster Nav-channel mutant, paraShu. Our analyses using chromosome deficiencies, gene-specific RNA interference, and single-gene mutants revealed that a null allele of glutathione S-transferase S1 (GstS1) dominantly suppresses paraShu phenotypes. Reduced GstS1 function also suppressed phenotypes of other seizure-prone Nav-channel mutants, paraGEFS+ and parabss. Notably, paraShu mutants expressed 50% less GstS1 than wild-type flies, further supporting the notion that paraShu and GstS1 interact functionally. Introduction of a loss-of-function GstS1 mutation into a paraShu background led to up- and down-regulation of various genes, with those encoding cytochrome P450 (CYP) enzymes most significantly over-represented in this group. Because GstS1 is a fly ortholog of mammalian hematopoietic prostaglandin D synthase, and in mammals CYPs are involved in the oxygenation of polyunsaturated fatty acids including prostaglandins, our results raise the intriguing possibility that bioactive lipids play a role in GstS1-mediated suppression of paraShu phenotypes.

genetics↗

bioRxiv2019

Tet2 negatively regulates memory fidelity

Despite being fully differentiated, DNA methylation is dynamically regulated in post-mitotic glutamatergic neurons in the CA1 of the hippocampus through competing active DNA methylation and de-methylation, a process that regulates neuronal plasticity. Active DNA methylation after learning is necessary for long-term memory formation, and active DNA de-methylation by the TET enzymes has been implicated as a counter-regulator of that biochemical process. We demonstrate that Tet2 functions in the CA1 as a negative regulator of long-term memory, whereby its knockdown across the CA1 or haploinsufficiency in glutamatergic neurons enhances the fidelity of hippocampal-dependent spatial and associative memory. Loci of altered DNA methylation were then determined using whole genome bisulfite sequencing from glutamatergic Tet2 haploinsufficient CA1 tissue, which revealed hypermethylation in the promoters of genes known to be transcriptionally regulated after experiential learning. This study demonstrates a link between Tet2 activity at genes important for memory formation in CA1 glutamatergic neurons and memory fidelity.

neuroscience↗