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The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPR mt ) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPR mt . HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPR mt , innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPR mt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPR mt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPR mt ). Here the authors show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC), coordinates with the genome organizer DVE-1 to activate UPR mt and modulate mitochondrial homeostasis.

Key Points Histone acetylation is an epigenetic modification that is unequivocally associated with increasing the propensity for gene transcription. As gene transcription is a crucial feature of long-lasting forms of memories, increments in histone acetylation generally favour learning and memory, and can be considered molecular memory aids. Histone acetylation readily responds to neuronal activity in terms of neuronal depolarization and synaptic plasticity. So far, two pathways that mediate this response have been identified: the mitogen-activated protein kinase (MAPK) pathway and the dissociation of histone deacetylase 2 (HDAC2) from the chromatin. A reduction in histone acetylation has been causally implicated in memory impairment associated with neurodegeneration, ageing and neurodevelopment disorders such as Rubinstein–Taybi syndrome. From these studies, a gain-of-function of HDAC2 and a loss-of-function of the histone acetyl transferase cyclic AMP-responsive element-binding (CREB)-binding protein (CBP) emerge as chief culprits. The reduction of histone acetylation can be counteracted by the use of small molecule inhibitors of HDACs, so-called HDAC inhibitors (HDACis). Several HDACis have already been proven successful in rescuing cognitive deficits in animal models of neurodegeneration, Alzheimer's disease, ageing, and Rubinstein–Taybi syndrome, and might thus constitute a new template for pharmacological strategies against cognitive impairments. Although their precise mode of action is still not fully characterized, HDACis might act through a process called epigenetic priming, a term originally used in cancer research. Epigenetic priming refers to a support-only mode of action of HDACis, whereby HDACis alone have little effect (on histone acetylation and gene transcription), but when applied in conjunction with ongoing treatments that increase gene expression programmes, HDACis further potentiate them. concept of epigenetic priming can be applied to neuroplasticity as well, in that HDACs would further support neuronal activity-driven gene expression programmes while having little or no effect on genes with constant rates of transcription. Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms such as histone acetylation. Gräff and Tsai review the roles of histone acetylation in memory and consider whether histone deacetylase inhibitors might have promise as therapeutic interventions against cognitive frailty. Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.

Background Vascular endothelial growth factor (VEGF) is one of the most powerful proangiogenic factors and plays an important role in multiple diseases. Increased glycolytic rates and lactate accumulation are associated with pathological angiogenesis. Results Here, we show that a feedback loop between H3K9 lactylation (H3K9la) and histone deacetylase 2 (HDAC2) in endothelial cells drives VEGF-induced angiogenesis. We find that the H3K9la levels are upregulated in endothelial cells in response to VEGF stimulation. Pharmacological inhibition of glycolysis decreases H3K9 lactylation and attenuates neovascularization. CUT& Tag analysis reveals that H3K9la is enriched at the promoters of a set of angiogenic genes and promotes their transcription. Interestingly, we find that hyperlactylation of H3K9 inhibits expression of the lactylation eraser HDAC2, whereas overexpression of HDAC2 decreases H3K9 lactylation and suppresses angiogenesis. Conclusions Collectively, our study illustrates that H3K9la is important for VEGF-induced angiogenesis, and interruption of the H3K9la/HDAC2 feedback loop may represent a novel therapeutic method for treating pathological neovascularization.

We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival. Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, and podocyte-associated Hdac1 and Hdac2 genetic ablation improved proteinuria and glomerulosclerosis. Podocyte early growth response 1 (EGR1) was increased in proteinuric patients and mice in an HDAC1- and HDAC2-dependent manner. Loss of EGR1 in mice reduced proteinuria and glomerulosclerosis. Longitudinal analysis of the multicenter Veterans Aging Cohort Study demonstrated a 30% reduction in mean annual loss of estimated glomerular filtration rate, and this effect was more pronounced in proteinuric patients receiving valproic acid. These results strongly suggest that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases through the regulation of EGR1.

The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention.

In carpenter ants, separate behavioral classes, known as castes, are determined by the epigenetic regulation of genes. Simola et al. treated ants of different castes with drugs that affected histone acetylation. Reducing histone acetylation stimulated scouting and foraging behavior. The foraging and scouting behaviors of young ants were permanently changed by directly injecting their brains with histone acetylation inhibitors. Science , this issue p. 10.1126/science.aac6633 Changes in histone acetylation explain differences in the foraging and scouting patterns of different castes of carpenter ants. Eusocial insects organize themselves into behavioral castes whose regulation has been proposed to involve epigenetic processes, including histone modification. In the carpenter ant Camponotus floridanus , morphologically distinct worker castes called minors and majors exhibit pronounced differences in foraging and scouting behaviors. We found that these behaviors are regulated by histone acetylation likely catalyzed by the conserved acetyltransferase CBP. Transcriptome and chromatin analysis in brains of scouting minors fed pharmacological inhibitors of CBP and histone deacetylases (HDACs) revealed hundreds of genes linked to hyperacetylated regions targeted by CBP. Majors rarely forage, but injection of a HDAC inhibitor or small interfering RNAs against the HDAC Rpd3 into young major brains induced and sustained foraging in a CBP-dependent manner. Our results suggest that behavioral plasticity in animals may be regulated in an epigenetic manner via histone modification.

Histone deacetylases (HDACs) are epigenetic regulators frequently altered in cancer. Here we report that overexpression of HDAC1 /2 occurs in Hepatocellular Carcinoma (HCC) patients, correlating with poor prognosis. We show that romidepsin, a class-I HDAC inhibitor, elicits a combinatorial perturbation of distinct molecular processes in HCC cells, altering lipid composition, mitotic spindle machinery, and levels of cell cycle/survival signals. Collectively, these alterations lead HCC cells to a vulnerable state, conferring dependency to receptor tyrosine kinase (RTK) signalling support. The cytostatic effects of romidepsin alone is converted into cytotoxicity by the RTK inhibitor cabozantinib in HCC models. We document that romidepsin+cabozantibib confers an immune-stimulatory profile in Alb-R26 Met mouse models, with direct effects on primary human dendritic cell maturation in vitro. Our findings put forward the intricate crosstalk between epigenetics, metabolism, and immune response in cancer. The broad action of romidepsin on distinct cellular functions highlights its therapeutic potential for HCC treatment. Targeting histone deacetylases (HDACs) alone has shown limited success in solid tumours. Here, authors report that the HDAC1/2 inhibitor romidepsin confers responsiveness to receptor tyrosine kinase inhibitors, with enhanced therapeutic effects in models of hepatocellular carcinoma, leading to tumour regression and an immune-stimulatory profile.

Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we unveil a genetic interaction between histone deacetylase 1 ( HDAC1 ) and HDAC2 , wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal deletions that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic disruption or dTAG-mediated degradation, we show that targeting HDAC2 suppresses the growth of HDAC1 -deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2–NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders that could leverage HDAC1/2 synthetic lethality to target NuRD vulnerabilities. Altogether, we identify HDAC1 / 2 collateral synthetic lethality as a potential therapeutic target and reveal an unexplored mechanism for targeting NuRD-associated cancer dependencies. Here, the authors show that HDAC1 and HDAC2 genetically interact, with each paralog being synthetically lethal with hemizygous deletion of the other. Mechanistically, HDAC1/2 co-deficiency leads to degradation of the NuRD complex, decreased chromatin accessibility and aberrant enhancer-based interactions.

The peripheral nervous system (PNS) regenerates after injury. However, regeneration is often compromised in the case of large lesions, and the speed of axon reconnection to their target is critical for successful functional recovery. After injury, mature Schwann cells (SCs) convert into repair cells that foster axonal regrowth, and redifferentiate to rebuild myelin. These processes require the regulation of several transcription factors, but the driving mechanisms remain partially understood. Here we identify an early response to nerve injury controlled by histone deacetylase 2 (HDAC2), which coordinates the action of other chromatin-remodelling enzymes to induce the upregulation of Oct6, a key transcription factor for SC development. Inactivating this mechanism using mouse genetics allows earlier conversion into repair cells and leads to faster axonal regrowth, but impairs remyelination. Consistently, short-term HDAC1/2 inhibitor treatment early after lesion accelerates functional recovery and enhances regeneration, thereby identifying a new therapeutic strategy to improve PNS regeneration after lesion. Brügger et al . identify part of the molecular machinery that controls Schwann cell development after peripheral nerve injury. Inhibiting HDAC1/2 early after injury enhances nerve regeneration and promotes functional recovery.

Hedgehog signalling is crucial for development and is deregulated in several tumours, including medulloblastoma. Regulation of the transcriptional activity of Gli (glioma-associated oncogene) proteins, effectors of the Hedgehog pathway, is poorly understood. We show here that Gli1 and Gli2 are acetylated proteins and that their HDAC-mediated deacetylation promotes transcriptional activation and sustains a positive autoregulatory loop through Hedgehog-induced upregulation of HDAC1. This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist lost in human medulloblastoma. Whereas high HDAC1 and low REN expression in neural progenitors and medulloblastomas correlates with active Hedgehog signalling, loss of HDAC activity suppresses Hedgehog-dependent growth of neural progenitors and tumour cells. Consistent with this, abrogation of Gli1 acetylation enhances cellular proliferation and transformation. These data identify an integrated HDAC- and ubiquitin-mediated circuitry, where acetylation of Gli proteins functions as an unexpected key transcriptional checkpoint of Hedgehog signalling.