Biology subjects

Rodriguez-Acevedo, K. L.

Publications and source records attributed to Rodriguez-Acevedo, K. L..

7 recordsLinked to original sources

bioRxiv2026

Neuron-specific epigenetic repression of Cdk5 impairs hippocampal-dependent memory in male and female mice

Biological sex regulates fundamental neurobiology, as well as the etiology and prevalence of neuropsychiatric disorders. Cyclin-dependent kinase 5 (Cdk5) is a neuronally enriched kinase that regulates synaptic plasticity, neuronal homeostasis, and hippocampal-dependent memory. While Cdk5 protein activity is necessary and sufficient to promote memory in male rodents, its role in females and its gene regulation in either sex remain poorly understood. In males, Cdk5 protein inhibition impairs fear memory. We previously showed that fear conditioning activates Cdk5 gene expression and increases permissive chromatin acetylation in male, but not female hippocampus. We hypothesize that Cdk5 gene repression would impair fear memory in males. We developed an excitatory neuron-specific, CRISPR/dCas9-HDAC3 epigenetic editing tool to target histone acetylation at the endogenous Cdk5 promoter. This strategy reduced histone acetylation and decreased Cdk5 mRNA, protein, and kinase activity in both sexes. Interestingly, Cdk5 repression in hippocampal neurons impaired fear and spatial memory in both male and female mice. Targeted deacetylation also evicted the transcription factor CREB1 from the Cdk5 promoter, revealing a link between histone acetylation and Cdk5 transcriptional activation. These findings demonstrate that Cdk5 acetylation in neurons is necessary for hippocampal memory in both sexes, providing new insight into sex-specific epigenetic regulation of memory.

molecular biology↗

bioRxiv2025

Hippocampal Cdk5 is regulated by distinct stress paradigms in male and female mice

Anxiety and mood disorders have been rising since the COVID-19 pandemic, marked by social isolation and stress. Women are disproportionately affected by stress-related disorders, yet the interaction between social isolation and stress remains understudied in females. Cyclin-dependent kinase 5 (Cdk5) is an atypical kinase that exhibits sex-specific regulation following various stressors but is studied almost exclusively in males. To complement these findings, we examined sex differences in mouse hippocampal Cdk5 mRNA and protein following short and long restraint stress with or without concomitant social isolation stress. While short restraint stress was sufficient to promote anxiety-like in both male and female mice, it did not alter Cdk5. Rather, hippocampal Cdk5 mRNA increased only after a longer restraint stress duration followed by social isolation, and only in male mice. Hippocampal Cdk5 protein also shifted from the cytosolic to the nuclear compartment only in male hippocampus. Surprisingly, repeated restraint stress promoted exploratory behavior in both group-housed and socially isolated male and female mice. Social isolation alone increased Cdk5 protein in females only. Finally, under all conditions, female mice were less immobile and more exploratory than male mice. Together, these results provide new insight into the sex-specific regulation of hippocampal Cdk5 by the combination of psychological and environmental stressors. HighlightsO_LIShort 10-minute restraint stress induced anxiety-like behavior in both sexes without altering hippocampal Cdk5 expression. C_LIO_LILong 1-hour restraint stress with post-stress social isolation elicited male-specific hippocampal Cdk5 transcription and Cdk5 cytosolic-to-nuclear protein redistribution. C_LIO_LIRepeated restraint stress increased exploratory behavior in both sexes, suggesting altered stress responsiveness. C_LIO_LISocial isolation interacted with repeated restraint to alter hippocampal Cdk5 protein levels selectively in females. C_LI

neuroscience↗

bioRxiv2025

Epigenetic editing of Cartpt promotes acquisition and extinction of cocaine memory

In classic disease models, removing a pathological insult restores homeostasis. Yet, addiction persists far beyond the period of active drug use. Cocaine abstinence induces changes in gene expression and neuronal signaling in reward-related brain regions that limit recovery during abstinence. We found that 2 weeks of abstinence increased Cartpt (cocaine- and amphetamine-regulated transcript) in the mouse nucleus accumbens and decreased repressive H3K27me3 at the Cartpt locus. While endogenous CART peptide is best described for its anorexigenic function, it is also implicated in human addiction and dopamine homeostasis. To test the causal relevance of Cartpt chromatin remodeling, we used CRISPR-based epigenetic editing tools, dCas9-FOG1 and dCas9-JMJC-ZF, to manipulate H3K27me3 at Cartpt in vivo. Enriching H3K27me3 in D1 neurons repressed Cartpt expression and augmented acquisition and extinction of cocaine preference. These results show that CRISPR epigenetic editing can recapitulate endogenous chromatin states to modulate addiction-related behavior, highlighting broad therapeutic potential of both Cartpt and epigenetic editing. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/689329v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1b84229org.highwire.dtl.DTLVardef@1ffc2d7org.highwire.dtl.DTLVardef@50cf00org.highwire.dtl.DTLVardef@1462d10_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

CRISPR-mediated transcriptional activation as a mutation-independent therapeutic strategy for SYNGAP1-related intellectual disability

Synaptic Ras GTPase-activating protein (SynGAP) regulates synaptic strength and neuronal signaling, with essential roles in cortical development and synaptic plasticity. Heterozygous loss-of-function variants in SYNGAP1 cause SYNGAP1-related intellectual disability (SRID), a severe neurodevelopmental disorder characterized by epilepsy, developmental delay, and autism. SYNGAP1 mutations often result in haploinsufficiency, providing a strong rationale for gene-targeted therapies. However, no treatment currently addresses the underlying genetic cause of SRID. Here, we developed a CRISPR-mediated transcriptional activation (CRISPRa) approach to upregulate the functional Syngap1 allele in a SRID mouse model. CRISPRa activated Syngap1, normalized SynGAP protein expression and downstream signaling, and rescued working memory deficits. We validated the translational potential of this strategy in human induced pluripotent stem cell (hiPSC)-derived excitatory cortical neurons. CRISPRa rescued SYNGAP1 in two distinct loss-of-function variant lines. Together, these findings demonstrate the feasibility of mutation-independent transcriptional activation as a therapeutic approach for SRID and its broader applicability to haploinsufficiency disorders.

neuroscience↗

bioRxiv2025

Unexpected mechanisms of sex-specific memory vulnerabilities to acute traumatic stress

It is increasingly recognized that severe acute traumatic events (e.g., mass shooting, natural disasters) can provoke enduring memory disturbances, and these problems are more common in women. We probed the fundamental sex differences underlying memory vulnerability to acute traumatic stress (ATS), focusing on the role of the sex hormone, estrogen (17{beta}-estradiol) and its receptor signaling in hippocampus. Surprisingly, high physiological hippocampal estrogen levels were required for ATS-induced episodic memory disruption and the concurrent sensitization and generalization of fear memories in both male and female mice. Pharmacological and transgenic approaches demonstrated signaling via estrogen receptor (ER) in males and, in contrast, ER{beta} in females, as the mechanisms for these memory problems. Finally, identify distinct hippocampal chromatin states governed by sex and estrogen levels, which may confer an enduring vulnerability to post-traumatic memory disturbances in females.

neuroscience↗

bioRxiv2025

Xist RNA Dependent and Independent Mechanisms Regulate Dynamic X Chromosome Inactivation in B Lymphocytes

X-Chromosome Inactivation (XCI) involves epigenetic pathways to equalize X-linked gene expression between female and male mammals. XCI is dynamic in female B cells, as cytological enrichment of Xist RNA and heterochromatic marks on the inactive X-chromosome (Xi) are absent in naive B cells yet return following mitogenic stimulation. Here, we asked whether any heterochromatic histone marks are present on the Xi in naive B cells, and whether Xist RNA is required for their deposition and retention following stimulation. We find that the Xi in naive B cells is depleted for H2AK119Ub and H3K9me3 but enriched for DNA methylation and H3K27me3, which maintain an Xist RNA-dependent epigenetic memory of XCI. Upon stimulation, Xist-independent H3K27me3 and Xist-dependent H2AK119Ub modifications accumulate across the Xi with temporal and spatial specificity. Our findings reveal the importance of Xist RNA, H3K27me3, and H2AK119Ub marks for the epigenetic integrity of X-linked genes across the Xi following female B cell stimulation.

genetics↗

bioRxiv2019

Conservation of an Ancient Oxidation Response That Controls Archaeal Epigenetic Traits Through Chromatin Protein Networks

Epigenetic variants of the archaeon Sulfolobus solfataricus called SARC have evolved heritable traits including extreme acid resistance, enhanced genome integrity and a conserved \"SARC\" transcriptome related to acid resistance. These traits appear to result from altered chromatin protein function related to the heritable hypomethylation of chromatin proteins Cren7 and Sso7D. To clarify how this might occur, ChIPseq and Affinity Purification Mass Spectrometry (AP-MS) were used to compare Cren7 and Sso7D genome binding sites and protein networks between lineages (wild type and SARC) and culture pH (pH 1 and 3). All SARC transcriptome loci were bound by these chromatin proteins but with invariant patterns indicating binding alone was insufficient to mediate the SARC traits. In contrast, chromosome association varied at other loci. Quantitative AP-MS was then used to identify protein interaction networks and these included transcription and DNA repair proteins implicated in the evolved heritable traits that varied in abundance between SARC and wild type strains. Protein networks included most of the S-adenosylmethionine (SAM) synthesis pathway including serine hydroxymethyltransferase (SHMT), whose abundance varied widely with culture pH. Because epigenetic marks are coupled to SAM pools and oxidative stress in eukaryotes, occurrence of a similar process was investigated here. Archaeal SAM pools were depleted by treatment with SAM pathway inhibitors, acid or oxidative stress and, like eukaryotes, levels were raised by vitamin B12 and methionine supplementation. We propose that in archaea, oxidation-induced SAM pool depletion acting through an SHMT sensor, drove chromatin protein hypomethylation and thereby protein network changes that established the evolved SARC epigenetic traits.\n\nSignificance StatementArchaea and eukaryotes share many molecular processes, including chromatin-mediated epigenetic inheritance of traits. As with eukaryotes, archaeal protein complexes were formed between trait-related proteins and chromatin proteins, subject to chromatin protein methylation state. Oxidation-induced depletion of S-adenosylmethionine (SAM) pools likely resulted in chromatin protein hypomethylation. Subsequent chromatin enrichment of serine hydroxymethyltransferase as a response to oxidative stress could modulate methylation at specific genomic loci. The interplay between archaeal metabolism and chromatin appear consistent with patterns observed in eukaryotes and indicate the existence of an ancient oxidation signal transduction pathway controlling epigenetics.

microbiology↗