Biology subjects

Berger, S. L.

Publications and source records attributed to Berger, S. L..

At least 19 recordsLinked to original sources

bioRxiv2026

Expanding the HIF-2α proteomic interactome with TurboID proximity labeling.

The transcription factor HIF2 is a central regulator of cellular adaptation to hypoxia, orchestrating gene expression programs that control angiogenesis, erythropoiesis, and metabolic reprogramming, and is famously overexpressed in cancers such as clear cell Renal Cell Carcinoma (ccRCC). While the gene targets of HIF2 have been extensively characterized, the composition and dynamics of its protein interaction network remain less well defined. In this study, we sought to systematically characterize proteins associated with HIF2 using two distinct proteomic approaches, enabling the identification of both stable binding partners and transient or indirect interactors. We integrated affinity purification mass spectrometry with proximity labeling strategies, thus expanding the existing interactome of HIF2 to include uniquely identified proteins and complexes such as members of the nuclear pore complex. Across both immunoprecipitation mass spectrometry (IP MS) and TurboID MS, we identified 888 and 1,048 proteins, respectively. We applied stringent filtering criteria to refine both datatsets, yielding a dataset of 329 HIF2 interacting proteins, approximately 75% of which have yet to be documented as HIF2 interactors. We queried this set across publicly available cancer genomics and proteomics datasets and detected expression of our interactors in breast cancer and ccRCC tumor proteomes. These findings led us to identify GRHL2 and KIF4A as proteomic interactors that contribute to poor patient survival in breast cancer. Taken together, we herein provide a comprehensive resource of HIF2 interacting proteins which provide insights into the mechanisms by which HIF2 drives disease progression.

biochemistry↗

bioRxiv2025

SWING domains prime chromatin for nuclear body mediated gene regulation

Nuclear speckles have long been recognized as RNA-rich nuclear bodies, yet their role in genome organization and gene regulation remains incompletely understood. Using a rapid dTAG-mediated degradation system to simultaneously deplete SON and SRRM2--the core structural components of nuclear speckles--we identify a novel class of genomic regions, which we term SWING regions. Upon speckle disruption, SWING regions relocate to the nuclear periphery and acquire repressive histone marks such as H3K9me3, accompanied by gene downregulation, particularly of genes involved in developmental pathways. Consistent with this, depletion of Lamin A reduces lamina association of SWING regions and enhances their association with nuclear speckles, supporting a bidirectional balance between these two nuclear compartments. Notably, human mutations in SON and SRRM2 are associated with neurodevelopmental disorders characterized by intellectual disability and global developmental delay. Patient-derived cells bearing such mutations similarly exhibit SWING-region relocalization and gene repression, underlining a role for speckles in developmental gene regulation. We also report that drug-induced speckle rejuvenation partially rescues aberrant SWING-region localization to the nuclear lamina in patient-derived cells and iPSCs with acute depletion of SON. These findings identify SWING regions as an intermediate chromatin state positioned between nuclear speckles and the lamina, maintained by opposing functions from both structures. Our work reveals a mechanism underlying the contribution of nuclear bodies to 3D genome organization, highlights the importance of nuclear speckles and SWING regions in developmental regulation, and provides a potential therapeutic intervention in speckle dysfunction. Impact StatementIdentification of nuclear speckles as determinants of specific 3D genome organization. Demonstration of functional interactions between opposing nuclear structures (speckle versus lamina) through SWING regions. Establishment of developmental and human disease relevance of speckle-mediated genome organization. Providing potential avenues for therapeutic intervention in speckleopathies.

genetics↗

bioRxiv2025

Deciphering the role of histone modifications in memory and exhausted CD8 T cells

Exhausted CD8 T cells (TEX) arising during chronic infections and cancer have reduced functional capacity and limited fate flexibility that prevents optimal disease control and response to immunotherapies. Compared to memory (TMEM) cells, TEX have a unique open chromatin landscape underlying a distinct gene expression program. How TEX transcriptional and epigenetic landscapes are regulated through histone post-translational modifications (hPTMs) remains unclear. Here, we profiled key activating (H3K27ac and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in naive CD8 T cells (TN), TMEM and TEX. We identified H3K27ac-associated super-enhancers that distinguish TN, TMEM and TEX, along with key transcription factor networks predicted to regulate these different transcriptional landscapes. Promoters of some key genes were poised in TN, but activated in TMEM or TEX whereas other genes poised in TN were repressed in TMEM or TEX, indicating that both repression and activation of poised genes may enforce these distinct cell states. Moreover, narrow peaks of repressive H3K9me3 were associated with increased gene expression in TEX, suggesting an atypical role for this modification. These data indicate that beyond chromatin accessibility, hPTMs differentially regulate specific gene expression programs of TEX compared to TMEM through both activating and repressive pathways.

immunology↗

bioRxiv2024

Neuropeptides specify and reprogram division of labor in the leafcutter ant Atta cephalotes

Social insects offer powerful models to investigate the mechanistic foundation of elaborate individual behaviors comprising a cooperative community. Workers of the leafcutter ant genus Atta provide an extreme example of behavioral segregation among many phenotypically distinct worker types. We utilize the complex worker system of Atta cephalotes to test the molecular underpinnings of behavioral programming and, in particular, the extent of plasticity to reprogramming. We identify specific neuropeptides as mediators of worker division of labor in A. cephalotes, finding two neuropeptides associated with characteristic behaviors of leafcutting and of brood care. Manipulation via genetic knockdown or by injection of these neuropeptides led to stark loss or gain of each behavior and to transcriptomic shifts in the predicted direction, that is, towards gene pathways expressed in the natural caste. We also compare specific A. cephalotes worker transcriptomes with those of orthologous workers of the eusocial mammal, the naked mole rat H. gaber, revealing global similarities between caste-biased expression and link to specific roles of our studied neuropeptides in ants. This work underscores the essential function of neuropeptides in establishing complex social behavior and a remarkable plasticity among individual behavioral types.

molecular biology↗

bioRxiv2024

The chromatin conformation landscape of Alzheimer's disease

We have been investigating epigenetic alterations in the brain during human aging and Alzheimers disease (AD), and have evidence for histone acetylation both protecting the aging epigenome and driving AD. Here we extend our studies to chromatin architecture via looping studies, and with binding studies of key proteins required for looping: CTCF and RAD21. We detected changes in CTCF and RAD21 levels and localization, finding major changes in CTCF in AD compared to fewer changes in healthy aging. In our study of 3D genome conformation changes, we identified stable topological associating domains (TADs) in Old and AD; in contrast, in AD, there is loss of interaction at genomic sites/loops within TADs, likely reflecting the loss of CTCF. We identified genes and potential transcription factor binding at the loops that are lost in AD. in addition, we found enrichment of CTCF peak losses for AD eQTLs, suggesting that architectural dysfunction has a role in Alzheimers. Functional experiments lowering the homologues of several key genes in a Drosophila model of A{beta}42 toxicity exacerbate neurodegeneration. Taken together, these data indicate both functional protections and losses occur in the Alzheimers brain genome compared to normal aging.

neuroscience↗

bioRxiv2024

ACSS2 contributes to transcriptional regulation in Cajal-Retzius cells in a mouse model of Alzheimer's disease

Dysregulation of histone acetylation in the brain has emerged as a major contributor to human Alzheimers disease (AD). The mechanisms by which these protective or risk-conferring epigenetic marks are established and maintained are under intense investigation. ACSS2 (Acetyl-CoA Synthetase 2) is a key metabolic enzyme that is chromatin-associated in neurons. ACSS2 is recruited to specific promoters and generates a local pool of acetyl-CoA from acetate, thereby fueling histone acetylation and driving the expression of neuronal genes that regulate learning and memory. Here, we examine the contribution of ACSS2-mediated histone acetylation to AD-related molecular and behavioral outcomes. Using a mouse model of human pathological AD-Tau injection, we show that loss of ACSS2 exacerbates Tau-related memory impairments, while dietary supplementation of acetate rescues learning in an ACSS2-dependent manner. Combining state-of-the-art proteomic and genomic approaches, we demonstrate that this effect is accompanied by ACSS2-dependent incorporation of acetate into hippocampal histone acetylation, which facilitates gene expression programs related to learning. Further, we identify Cajal-Retzius neurons as a critical hippocampal neuronal population affected, exhibiting the largest epigenetic and transcriptional dysregulation. Overall, these results reveal ACSS2 as a key neuroprotective metabolic enzyme, dysregulation of which might play an important role in the etiology of human AD, and guide the development of future therapies for AD and related dementia.

neuroscience↗

bioRxiv2024

TET2 regulates early and late transitions in exhausted CD8+ T-cell differentiation and limits CAR T-cell function

CD8+ T-cell exhaustion hampers disease control in cancer and chronic infections and limits efficacy of T-cell-based therapies, such as CAR T-cells. Epigenetic reprogramming of CAR T-cells by targeting TET2, a methylcytosine dioxygenase that mediates active DNA demethylation, has shown therapeutic potential; however, the role of TET2 in exhausted T-cell (TEX) development is unclear. In CAR T-cell exhaustion models and chronic LCMV infection, TET2 drove the conversion from stem cell-like, self-renewing TEX progenitors towards terminally differentiated and effector (TEFF)-like TEX. In mouse T-cells, TET2-deficient terminally differentiated TEX retained aspects of TEX progenitor biology, alongside decreased expression of the transcription factor TOX, suggesting that TET2 potentiates terminal exhaustion. TET2 also enforced a TEFF-like terminally differentiated CD8+ T-cell state in the early bifurcation between TEFF and TEX, indicating a broad role for TET2 in mediating the acquisition of an effector biology program that could be exploited therapeutically. Finally, we developed a clinically actionable strategy for TET2- targeted CAR T-cells, using CRISPR/Cas9 editing and site-specific adeno-associated virus transduction to simultaneously knock-in a CAR at the TRAC locus and a functional safety switch within TET2. Disruption of TET2 with this safety switch in CAR T-cells restrained terminal TEX differentiation in vitro and enhanced anti-tumor responses in vivo. Thus, TET2 regulates pivotal fate transitions in TEX differentiation and can be targeted with a safety mechanism in CAR T-cells for improved tumor control and risk mitigation. One Sentence SummaryModulation of exhausted CD8+ T-cell differentiation by targeting TET2 improves therapeutic potential of CAR T-cells in cancer.

immunology↗

bioRxiv2024

ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

Epigenetic mechanisms, including histone acetylation, are pivotal for learning and memory, with a role in neuronal function in Alzheimers disease and Related Dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme that generates acetyl-CoA, is central to histone acetylation and gene regulation, particularly in neurons, due to their unique metabolic demands and postmitotic state. ACSS2 can be recruited to the nucleus and chromatin, locally supplying acetyl-CoA to directly fuel histone acetyltransferase enzymes and key neuronal gene expression. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously we showed that systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon these findings, we reveal that increasing histone acetylation through ACSS2 upregulation improves age-associated memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. We thus highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, providing a foundation for targeted therapeutics to enhance brain resilience and function. SummaryACSS2 upregulation protects neurons from disease and age-related decline by enhancing synaptic and longevity gene expression.

neuroscience↗

bioRxiv2023

Decreased voluntary alcohol intake and ventral striatal epigenetic and transcriptional remodeling in male Acss2 KO mice

Metabolic-epigenetic interactions are emerging as key pathways in regulating alcohol-related transcriptional changes in the brain. We previously demonstrated that this is mediated by the metabolic enzyme Acetyl-CoA synthetase 2 (Acss2), which is nuclear and chromatin-bound in neurons. Mice lacking Acss2 fail to deposit alcohol-derived acetate onto histones in the brain and show no conditioned place preference for ethanol reward. Here, we explored the role of this pathway during voluntary alcohol intake. We found that Acss2 KO mice consumed significantly less alcohol during drinking-in-the-dark, and this effect was primarily driven by males. We performed genome-wide transcriptional profiling of 7 key brain regions implicated in alcohol and drug use, and found that, following drinking, Acss2 KO mice exhibited blunted gene expression in the ventral striatum, and similar to the behavioral differences, transcriptional dysregulation was more pronounced in male mice. Further, we found that the gene expression changes were associated with depletion of ventral striatal histone acetylation (H3K27ac) in Acss2 KO mice compared to WT. Taken together, our data suggest that Acss2 plays an important role in orchestrating ventral striatal epigenetic and transcriptional changes during voluntary alcohol drinking, especially in males. Consequently, targeting this pathway could be a promising new therapeutic avenue.

neuroscience↗

bioRxiv2023

Histone acetylation in an Alzheimer's disease cell model promotes homeostatic amyloid-reducing pathways

Alzheimers Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. Dysregulation of epigenetic histone modifications may lead to expression of transcriptional programs that play a role either in protecting against disease genesis or in worsening of disease pathology. One such histone modification, acetylation of histone H3 lysine residue 27 (H3K27ac), is primarily localized to genomic enhancer regions and promotes active gene transcription. We previously discovered H3K27ac to be more abundant in AD patient brain tissue compared to the brains of age-matched non-demented controls. In this study, we use iPSC-neurons derived from familial AD patients with an amyloid precursor protein (APP) duplication (APPDup neurons) as a model to study the functional effect of lowering CBP/P300 enzymes that catalyze H3K27ac primarily at gene enhancers. We found that homeostatic amyloid-reducing genes were upregulated in the APPDup neurons compared to non- demented controls. We lowered CBP/P300 to reduce H3K27ac, which led to decreased expression of numerous of these homeostatic amyloid-reducing genes, along with increased extracellular secretion of a toxic amyloid-{beta} species, A{beta}(1-42). Our findings suggest that epigenomic histone acetylation, including H3K27ac, drives expression of compensatory genetic programs in response to AD-associated insults, specifically those resulting from APP duplication, and thus may play a role in mitigating AD pathology in neurons.

neuroscience↗

bioRxiv2023

Nuclear speckles regulate HIF-2α programs and correlate with patient survival in kidney cancer

Nuclear speckles are membrane-less bodies within the cell nucleus enriched in RNA biogenesis, processing, and export factors. In this study we investigated speckle phenotype variation in human cancer, finding a reproducible speckle signature, based on RNA expression of speckle-resident proteins, across >20 cancer types. Of these, clear cell renal cell carcinoma (ccRCC) exhibited a clear correlation between the presence of this speckle expression signature, imaging-based speckle phenotype, and clinical outcomes. ccRCC is typified by hyperactivation of the HIF-2 transcription factor, and we demonstrate here that HIF-2 drives physical association of a select subset of its target genes with nuclear speckles. Disruption of HIF-2-driven speckle association via deletion of its speckle targeting motifs (STMs)--defined in this study--led to defective induction of speckle-associating HIF-2 target genes without impacting non-speckle-associating HIF-2 target genes. We further identify the RNA export complex, TREX, as being specifically altered in speckle signature, and knockdown of key TREX component, ALYREF, also compromises speckle-associated gene expression. By integrating tissue culture functional studies with tumor genomic and imaging analysis, we show that HIF-2 gene regulatory programs are impacted by specific manipulation of speckle phenotype and by abrogation of speckle targeting abilities of HIF-2. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of a specific subset of HIF-2-regulated target genes that, in turn, influence patient outcomes. We also identify STMs in other transcription factors, suggesting that DNA-speckle targeting may be a general mechanism of gene regulation. HIGHLIGHTS- Nuclear speckles shown to reproducibly vary in cancer, predicting patient survival in ccRCC - HIF-2 drives DNA/gene-speckle contacts dependent on identified speckle targeting motifs within HIF-2 - Putative speckle targeting motifs are highly enriched among regulators of gene expression - Partitioning of transcription factor functional programs may be a major biological function of nuclear speckles

cancer biology↗

bioRxiv2023

CTCF/cohesin organize the ground state of chromatin-nuclear speckle association

The interchromatin space in the cell nucleus contains various membrane-less nuclear bodies. Recent findings indicate that nuclear speckles, comprising a distinct nuclear body, exhibit interactions with certain chromatin regions in a ground state. Key questions are how this ground state of chromatin-nuclear speckle association is established and what are the gene regulatory roles of this layer of nuclear organization. We report here that chromatin structural factors CTCF and cohesin are required for full ground state association between DNA and nuclear speckles. Disruption of ground state DNA-speckle contacts via either CTCF depletion or cohesin depletion had minor effects on basal level expression of speckle-associated genes, however we show strong negative effects on stimulus-dependent induction of speckle-associated genes. We identified a putative speckle targeting motif (STM) within cohesin subunit RAD21 and demonstrated that the STM is required for chromatin-nuclear speckle association. In contrast to reduction of CTCF or RAD21, depletion of the cohesin releasing factor WAPL stabilized cohesin on chromatin and DNA-speckle contacts, resulting in enhanced inducibility of speckle-associated genes. In addition, we observed disruption of chromatin-nuclear speckle association in patient derived cells with Cornelia de Lange syndrome (CdLS), a congenital neurodevelopmental diagnosis involving defective cohesin pathways, thus revealing nuclear speckles as an avenue for therapeutic inquiry. In summary, our findings reveal a mechanism to establish the ground organizational state of chromatin-speckle association, to promote gene inducibility, and with relevance to human disease.

genetics↗

bioRxiv2023

Histone chaperone HIRA, Promyelocytic Leukemia (PML) protein and p62/SQSTM1 coordinate to regulate inflammation during cell senescence and aging.

Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory Senescence-Associated Secretory Phenotype (SASP), is a cause of aging. In senescent cells, Cytoplasmic Chromatin Fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. PML protein organizes PML nuclear bodies (NBs), also involved in senescence and anti-viral immunity. The HIRA histone H3.3 chaperone localizes to PML NBs in senescent cells. Here, we show that HIRA and PML are essential for SASP expression, tightly linked to HIRAs localization to PML NBs. Inactivation of HIRA does not directly block expression of NF-{kappa}B target genes. Instead, an H3.3-independent HIRA function activates SASP through a CCF-cGAS-STING-TBK1-NF-{kappa}B pathway. HIRA physically interacts with p62/SQSTM1, an autophagy regulator and negative SASP regulator. HIRA and p62 co-localize in PML NBs, linked to their antagonistic regulation of SASP, with PML NBs controlling their spatial configuration. These results outline a role for HIRA and PML in regulation of SASP.

cell biology↗

bioRxiv2023

Dynamic enhancer interactome promotes senescence and aging

Gene expression programs are regulated by enhancers which act in a context-specific manner, and can reside at great distances from their target genes. Extensive three-dimensional (3D) genome reorganization occurs in senescence, but how enhancer interactomes are reconfigured during this process is just beginning to be understood. Here we generated high-resolution contact maps of active enhancers and their target genes, assessed chromatin accessibility, and established one-dimensional maps of various histone modifications and transcription factors to comprehensively understand the regulation of enhancer configuration during senescence. Hyper-connected enhancer communities/cliques formed around genes that are highly expressed and within essential gene pathways in each cell state. In addition, motif analysis indicates the involvement of specific transcription factors in hyper-connected regulatory elements in each condition; importantly, MafK, a bZIP family transcription factor, was upregulated in senescence, and reduced expression of MafK ameliorated the senescence phenotypes. Because the accumulation of senescent cells is a key feature of aging, we further investigated enhancer connectomes in the liver of young and aged mice. Hyper-connected enhancer communities were identified during aging, which regulate essential genes that maintain cell differentiation and homeostasis. These findings reveal that hyper-connected enhancer communities correlate with high gene expression in senescence and aging and provide potential hotspots for therapeutic intervention in aging and age-associated diseases.

molecular biology↗

bioRxiv2022

Hormonal gatekeeping via the blood brain barrier governs behavior

Here we reveal an unanticipated role of the blood-brain-barrier (BBB) in regulating complex social behavior in ants. Using scRNA-seq we find localization in the BBB of a key hormone-degrading enzyme called Juvenile hormone esterase (Jhe), and we show that this localization governs the level of Juvenile Hormone (JH3) entering the brain. Manipulation of the Jhe level reprograms the brain transcriptome between ant castes. While ant Jhe is retained and functions intracellularly within the BBB, we show that Drosophila Jhe is naturally extracellular. Heterologous expression of ant Jhe into the Drosophila BBB alters behavior in fly to mimic what is seen in ant. Most strikingly, manipulation of Jhe levels in ant reprograms complex behavior between worker castes. Our study thus uncovers a novel, potentially conserved role of the BBB serving as a molecular gatekeeper for a neurohormonal pathway that regulates social behavior.

neuroscience↗

bioRxiv2022

Enhanced STAT5a activation rewires exhausted CD8 T cells during chronic stimulation to acquire a hybrid durable effector like state

Rewiring exhausted CD8 T cells (TEX) towards more functional states is a major goal of cancer immunotherapy but has proven challenging due to the epigenetic stability of TEX. Indeed, TEX are epigenetically programmed by the transcription factor Tox. However, epigenetic changes continue to occur as TEX transition from progenitor (TEXprog), to intermediate (TEXint) and terminal (TEXterm) subsets, suggesting potential developmental flexibility in mature TEX subsets. By examining the transition of TEXprog into TEXint cells, we discovered a reciprocally antagonistic circuit between Stat5a and Tox in TEX cells. Stat5-activity controlled TEXint development, antagonized Tox, and instigated partial effector biology. Stat5 was also essential for TEX reinvigoration by PD-1 blockade. Indeed, temporal induction of Stat5-activity in TEX using an orthogonal IL-2/IL2R{beta}-pair fostered TEXint cell accumulation and synergized with PD-L1 blockade. Constitutive Stat5a activity (STAT5CA) antagonized Tox-dependent TEX epigenetic programming to generate a durable hybrid effector/NK-like population with enhanced tumor control. Finally, enforcing Stat5-signals in established TEXprog partially rewired the TEX epigenetic landscape towards the effector/memory lineage. Together, these data highlight therapeutic opportunities of manipulating Stat5 to rewire TEX towards a durably protective hybrid program.

immunology↗

bioRxiv2022

Spurious intragenic transcription is a hallmark of mammalian cellular senescence and tissue aging

Mammalian aging is characterized by the progressive loss of tissue integrity and function manifesting in ill health and increased risk for developing multiple chronic conditions. Accumulation of senescent cells in aging tissues partly contributes to this decline and targeted depletion of senescent cells in vivo ameliorates many age-related phenotypes. However, the fundamental molecular mechanisms responsible for the decline of cellular health and fitness during senescence and aging are largely unknown. In this study, we investigated whether chromatin-mediated loss of transcriptional fidelity, known to contribute to fitness and survival in yeast and worms, also occurs during human cellular senescence and mouse aging. Our findings reveal that aberrant transcription initiation inside genes is widespread in senescence and aging. It co-occurs with changes in the chromatin landscape and formation of non-canonical transcription start sites. Interventions that alter spurious transcripts have dramatic consequences on cellular health primarily affecting intracellular signal transduction pathways. We propose that spurious transcription is a conserved hallmark of aging that promotes a noisy transcriptome and degradation of coherent transcriptional networks.

genomics↗

bioRxiv2022

Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation

Histone acetylation is a key component in the consolidation of long-term fear memories. Epigenetic enzymes involved in histone acetylation, including histone acetyltransferases and deacetylases, have been put forward as potential pharmacological targets in the treatment of pathological fear memories, such as those that underlie post-traumatic stress disorder (PTSD). However, these enzymes typically play a ubiquitous role in gene regulation, which precludes the clinical use of systemic manipulations. Recently, we have found that a nuclear-localized metabolic enzyme, Acetyl-coA synthetase 2 (Acss2), modulates histone acetylation during learning and memory. Loss of Acss2 is well-tolerated in mice, with no impact on general health or baseline behavior. Here, we show that an Acss2 null mouse model shows reduced acquisition of long-term fear memories in assays of contextual and cued fear conditioning. We find that loss of Acss2 leads to consolidation-specific reductions in both histone acetylation and the expression of critical learning and memory-related genes in the dorsal hippocampus. Further, we show that systemic administration of blood-brain-barrier (BBB)-permeable Acss2 inhibitors during the consolidation window reduces fear memory formation in mice and rats, and also reduces anxiety in a predator-scent-stress (PSS) paradigm. Our findings suggest that Acss2 plays a critical role in the formation of fear memories, and represents a potential pharmacological target in the treatment of PTSD.

neuroscience↗