Phytohormone abscisic acid (ABA) induces the stomatal closure in plants under drought stress, a process requiring actin reorganization. Yet how ABA perception couples with cytoskeletal dynamics in stomatal closure remain...Phytohormone abscisic acid (ABA) induces the stomatal closure in plants under drought stress, a process requiring actin reorganization. Yet how ABA perception couples with cytoskeletal dynamics in stomatal closure remains unclear. In this study, we report that Arabidopsis cyclase-associated protein 1 (CAP1) functions as a negative regulator of ABA-induced drought responses through modulating actin network organization in Arabidopsis. Further analyses demonstrate that CAP1 interacts with RCAR12 suppresses actin filaments (F-actin) disassembly, whereas ABA disrupts the CAP1-RCAR12 interaction, thus recovering CAP1's depolymerization activity. Further, ABA-activated OST1 (OPEN STOMATA 1) phosphorylates CAP1 in Arabidopsis. OST1-mediated phosphorylation of CAP1 attenuates CAP1 binding to ADF4 and inhibits the ADF4-CAP1 complex. This inhibition leads to F-actin stabilization, which in turn maintains stomata in a closed state. This study demonstrates that CAP1 orchestrates ABA-induced stomatal closure under drought stress in Arabidopsis. Specifically, CAP1 acts by coupling ABA signaling to dynamic reorganization of actin cytoskeleton.
Homologous recombination (HR) is a DNA repair pathway that utilizes a template-based approach to repair double-strand breaks within the genome. Template use requires the exchange of individual DNA strands, which members...Homologous recombination (HR) is a DNA repair pathway that utilizes a template-based approach to repair double-strand breaks within the genome. Template use requires the exchange of individual DNA strands, which members of the RecA family of recombinases facilitate. Rad51 is a primary strand exchange factor in eukaryotes. During regular mitotic DNA repair, Rad51 is aided by the DNA translocase Rad54, which acts as a motor to remodel the template DNA and stabilize primary-strand exchange intermediates. The regulation of this activity remains incompletely understood. Here, we have identified a conserved site within the C-terminal region of Rad54. The mutation of this site creates a separation of function at early strand-exchange intermediates in vivo. Using this mutant protein, we identify a novel intermediate essential for stabilizing displacement loop (D-loop) structures. This precedes the removal of Rad51 and DNA extension. Based on our experiments, we hypothesize that this Rad54 mutant cannot stabilize Rad51-mediated strand-exchange intermediates due to slippage during translocation, leading to failure in DNA remodeling. Identifying a mutant that disrupts this intermediate before Rad51 removal unifies existing models of Rad54-mediated D-loop formation and extension.
During fertilization, haploid gametes combine to form a zygote. The male (sperm) and female (oocyte) gametes contribute a similar amount of DNA, but the oocyte contributes nearly all the cytoplasm. Oocytes are loaded wit...During fertilization, haploid gametes combine to form a zygote. The male (sperm) and female (oocyte) gametes contribute a similar amount of DNA, but the oocyte contributes nearly all the cytoplasm. Oocytes are loaded with maternal mRNAs thought to be essential for embryonic patterning after fertilization. A conserved suite of RNA-binding proteins (RBPs) regulates the spatiotemporal translation and stability of maternal mRNAs. POS-1 is a CCCH-type tandem zinc finger RBP expressed in fertilized Caenorhabditis elegans zygotes from maternally supplied mRNA. POS-1 accumulates in the posterior of the embryo where it promotes posterior cell fate. Here, we show that the pos-1 3' untranslated region (UTR) is essential for POS-1 patterning and contributes to maximal reproductive fecundity. We engineered a pos-1 mutant where most of the endogenous pos-1 3'UTR was removed using CRISPR genome editing. Our results show that the 3'UTR represses POS-1 expression in the maternal germline but increases POS-1 protein levels in embryos after fertilization. In a wild-type background, POS-1 repression via the 3'UTR has little impact on fertility. In a sensitized background, the deletion mutant has a complex pleiotropic phenotype where most adult homozygous progeny lack either one or both gonad arms. Most phenotypes become more penetrant at elevated temperature. Together, our results support an emerging model where the 3'UTRs of maternal transcripts, rather than being essential, contribute to reproductive robustness during stress.
Balancing growth and stress adaptation is essential for optimizing crop productivity, yet the transcriptional mechanisms underlying this trade-off in wheat remain poorly understood. Here, we identify the WRKY transcripti...Balancing growth and stress adaptation is essential for optimizing crop productivity, yet the transcriptional mechanisms underlying this trade-off in wheat remain poorly understood. Here, we identify the WRKY transcription factor TaWRKY58 as a key repressor coordinating plant architecture and drought response. Loss-of-function mutants of TaWRKY58 exhibit increased plant height and early flowering, accompanied by elevated gibberellin levels, while overexpression restores wild-type phenotypes. Under drought stress, TaWRKY58 represses soluble sugar accumulation, and its mutants show enhanced drought tolerance. Using DAP-seq, we identified genome-wide binding sites of TaWRKY58 and uncovered a W-box-like motif enriched in its target promoters. Electrophoretic mobility shift and dual-luciferase assays confirmed that TaWRKY58 directly binds to and represses two key targets: TaLRR, encoding a leucine-rich repeat protein, and TaBCS1, encoding a mitochondrial AAA⁺ ATPase. Mutants of TaLRR and TaBCS1 display dwarfism and drought hypersensitivity, respectively, mirroring aspects of the TaWRKY58 overexpression phenotype. Our data support a model in which TaWRKY58 functions as a transcriptional repressor in a coherent regulatory module that fine-tunes growth and stress adaptation by modulating signaling and energy metabolism. This mechanism offers a potential strategy for breeding wheat with optimized yield stability under fluctuating environments.
Emerging evidence reveals the pivotal involvement of mitochondrial metabolic dysregulation in glioblastoma (GBM) pathogenesis, considering mitochondrial metabolism as a potential therapeutic target. Nebivolol, a third-ge...Emerging evidence reveals the pivotal involvement of mitochondrial metabolic dysregulation in glioblastoma (GBM) pathogenesis, considering mitochondrial metabolism as a potential therapeutic target. Nebivolol, a third-generation β-adrenergic receptor antagonist clinically employed in cardiovascular diseases, has recently exhibited notable anti-neoplastic properties. Nevertheless, its therapeutic efficacy and mechanistic underpinnings in GBM remain largely unexplored. In this investigation, we comprehensively assessed the impact of nebivolol on GBM cellular proliferation and elucidated its molecular mechanisms. Our findings revealed that nebivolol markedly suppressed the proliferation and clonogenic abilities of multiple GBM cell lines, concomitant with cell cycle arrest and apoptotic induction. Mechanistically, nebivolol impaired mitochondrial respiratory chain complex I activity, diminished adenosine triphosphate (ATP) synthesis, and augmented ROS production, collectively precipitating neoplastic cell apoptosis. Furthermore, nebivolol attenuated AKT/mTOR/4EBP1 signaling cascade activation, thereby impeding GBM malignant proliferation. In vivo studies corroborated these observations, demonstrating that nebivolol administration significantly attenuated orthotopic GBM xenograft progression and extended survival in tumor-bearing murine models. This study delineates a novel dual mechanism whereby nebivolol exerts anti-GBM effects through concurrent modulation of mitochondrial bioenergetics and AKT/mTOR/4EBP1 signaling transduction. These results provide robust preclinical evidence supporting nebivolol's clinical repurposing for GBM therapy.
Protein kinases are key components of many signaling pathways that regulate cellular activities, and some of them are indispensable for the viability of cells. We used inducible gene deletion to assess the importance of...Protein kinases are key components of many signaling pathways that regulate cellular activities, and some of them are indispensable for the viability of cells. We used inducible gene deletion to assess the importance of a set of putative essential protein kinases for growth and viability of the pathogenic yeast Candida albicans and to get clues about the functions of uncharacterized essential kinases. We found that bud32Δ, ctk1Δ, rio1Δ, and rio2Δ mutants were viable but grew very slowly, explaining previous failures to generate homozygous deletion mutants. PTK2 was essential, but under certain conditions ptk2Δ mutants remained viable and over time could acquire suppressor mutations in the Ptk2-dependent plasma membrane ATPase Pma1 that restored growth. Deletion of the uncharacterized orf19.5376 was lethal and the null mutants formed pseudohyphae that lacked normal septa and eventually lysed, a phenotype that was phenocopied by auxin-induced protein depletion. The mutants were defective in septin organization, indicating that the orf19.5376-encoded kinase is functionally similar to the nonessential kinase Elm1 of Saccharomyces cerevisiae, but is indispensable for viability in C. albicans. Mutants lacking orf19.3456, which does not have a homolog in S. cerevisiae, were also nonviable and grew as aseptate, sometimes multinucleate hyphae before cell death. Co-immunoprecipitation followed by liquid chromatography-mass spectrometry identified a protein, encoded by the uncharacterized orf19.193, as a candidate regulatory subunit of the orf19.3456-encoded kinase, as mutants lacking this protein exhibited the same terminal phenotype as orf19.3456 mutants. These results provide strong evidence that instead of using a mitotic exit network (MEN) with only two kinases (Cdc15 and Dbf2), as was previously thought, C. albicans regulates septum formation and cytokinesis via a septation initiation network (SIN), known from fission yeast and filamentous fungi, which contains a protein kinase cascade consisting of the upstream kinase Cdc15, the orf19.3456-encoded kinase, and the downstream kinase Dbf2.
Epigenetic regulators shape chromatin landscapes, allowing cells to express distinct gene sets depending on cell-type, developmental stage or environmental cues. These regulatory complexes rely on interactions with seque...Epigenetic regulators shape chromatin landscapes, allowing cells to express distinct gene sets depending on cell-type, developmental stage or environmental cues. These regulatory complexes rely on interactions with sequence-specific DNA binding proteins, such as the small family of TELOMERE REPEAT BINDING FACTORS (TRBs). TRBs are components of chromatin regulatory complexes with opposing functions, such as the epigenetic repressors Polycomb Repressive Complex 2 (PRC2) and a JMJ14/NAC complex that respectively add and removes the repressive H3K27me3 and positive H3K4me3 modification, but also with the plant-specific PEAT complex that is linked to histone acetylation and gene activation. We dissected the partial redundancy between TRB1, TRB2 and TRB3 in target gene selection and interaction with different chromatin regulatory complexes. High redundancy of TRBs is suggested by major phenotypic changes that are only observed trb triple mutants; however, we found different target site preference between TRB1-3 and preferred partnership with chromatin complexes. Furthermore, TRB paralogs interacted with the NuA4 histone acetylation complex, both together with and in absence of PEAT. Among the three paralogs, TRB1 had more unique binding sites and correlated stronger with PEAT and NuA4 functions. In contrast, TRB2 and TRB3 were more dependent on the presence of bona fide telo-box motifs and were more likely to be found at PRC2 associated sites. Overall, we provide insight into the diverse roles of TRBs in epigenetic gene regulation and how their diversification contributes to their apparent redundancy, as well as their observed activating and repressing effects on gene expression.
Kalamara M, Bonsall A, Griffin J
… +10 more, Carneiro J, Gierlinski M, Eigentler L, Stevenson D, Wood A, Porter M, Dorfmueller HC, MacPhee CE, Abbott JC, Stanley-Wall NR
Kudoh A, Natsume S, Sugihara Y
… +15 more, Kato H, Abe A, Oikawa K, Shimizu M, Itoh K, Tsujimura M, Takano Y, Sakai T, Adachi H, Ohta A, Ohtsu M, Ishizaki T, Terachi T, Innan H, Terauchi R
Dioecious plants, which have distinct male and female individuals, constitute ~5% of angiosperm species and have emerged frequently and independently from hermaphroditic ancestors. Although recent molecular studies of se...Dioecious plants, which have distinct male and female individuals, constitute ~5% of angiosperm species and have emerged frequently and independently from hermaphroditic ancestors. Although recent molecular studies of sex determination have started to reveal the diversity of the genetic systems underlying dioecy, research on the evolution of dioecy is limited, especially in monocots. Here, we explore the molecular basis of sex determination in the monocot Dioscorea tokoro, a dioecious wild yam endemic to East Asia. Chromosome-scale and haplotype-resolved genome assemblies and linkage analysis suggested that this plant has a male heterogametic sex-determination (XY) system, with sex-determination regions located on chromosome 3. Sequence comparison between the X- and Y-chromosomes and read coverage analysis revealed X- and Y-specific regions in putative pericentromeric chromosome regions. Within the Y-specific region, we propose two candidate genes that are likely involved in sex determination: BLH9, encoding a homeobox protein, and HSP90, encoding a molecular chaperone. BLH9 functions in a similar way as AtBLH9 in Arabidopsis thaliana. BLH9 could be involved in suppression of female organ development, whereas HSP90 might be required for pollen development. These results shed light on the complex evolution of dioecy in plants.
Human birth weight is under stabilizing selection, seeking balance between extremes of high and low, thereby reducing fetal and maternal perinatal mortality risk. Certain combinations of maternal killer immunoglobulin-li...Human birth weight is under stabilizing selection, seeking balance between extremes of high and low, thereby reducing fetal and maternal perinatal mortality risk. Certain combinations of maternal killer immunoglobulin-like receptor (KIR) and paternally derived fetal human leuokocyte antigen-C (HLA-C) alleles were previously associated with higher risk of high and low birth weight in a study with limited sample size (n = 1,316). Using recently developed methods to impute HLA and KIR haplotypes using single nucleotide polymorphism (SNP) genotype data, we tested associations of fetal HLA and maternal KIR genotypes with offspring birth weight in a large sample. We imputed KIR haplotypes using the KIR*IMP imputation software in 10,602 mother-offspring pairs of European descent from singleton pregnancies from five studies. Using mixed linear regression models to account for mothers with multiple children, we tested associations between maternal KIR A vs B haplotypes (AA, AB/BA, BB genotypes) as well as copy number of activating receptor gene KIR2DS1 (0, 1, 2 copies of the gene) in the presence of fetal HLA C1/C2 alleles, and offspring birth weight. Associations were analyzed in each cohort before performing a meta-analysis to estimate the interaction effects between maternal KIR and fetal HLA-C2 on birth weight across the entire sample. The KIR haplotypes achieved imputation accuracy estimated at >95% in most of the cohorts. No interaction effects were observed between either the maternal A vs. B haplotype or the maternal KIR2DS1 locus and fetal HLA-C. When specifically trying to replicate the previously associated combination of maternal KIR2DS1 and paternally inherited fetal HLA-C2, there was a negligible change in offspring birth weight for each additional KIR2DS1 allele and HLA-C2 of paternal origin (7g lower birth weight per allele [95% CI: -54, 40], P = 0.78). We found little evidence of association between birth weight and maternal KIR haplotypes or fetal HLA-C2 and were unable to replicate previously reported findings. Our observations reinforce the importance of replication and the use of large sample sizes in the validation of genetic associations.
A Batista R, Durand E, Mörchen M
… +20 more, Azevedo-Favory J, Simon S, Dubin M, Kumar V, Lacoste E, Cruaud C, Blassiau C, Barois M, Holl AC, Ponitzki C, Faure N, Marande W, Vautrin S, Fobis-Loisy I, Aury JM, Legrand S, Krämer U, Lagrange T, Vekemans X, Castric V
Self-incompatibility in flowering plants is a common mechanism that prevents self-fertilization and promotes outcrossing. In Brassicaceae, the self-incompatibility locus is highly diverse, with many alleles arranged in a...Self-incompatibility in flowering plants is a common mechanism that prevents self-fertilization and promotes outcrossing. In Brassicaceae, the self-incompatibility locus is highly diverse, with many alleles arranged in a complex dominance hierarchy and exhibiting monoallelic expression in heterozygote individuals. Monoallelic expression of the pollen self-incompatibility gene is achieved through the action of sRNA precursors that resemble miRNAs, although the underlying molecular mechanisms remain elusive. Here, we engineered Arabidopsis thaliana lines expressing components of the Arabidopsis halleri self-incompatibility system, and used a reverse genetics approach to pinpoint the pathways underlying the function of these sRNA precursors. We showed that they trigger a robust decrease in transcript abundance of the recessive self-incompatibility genes, but not through the canonical transcriptional or post-transcriptional gene silencing pathways. Furthermore, we observed that single sRNA precursors are typically processed into hundreds of sRNA molecules with a variety of sizes, abundance levels and ARGONAUTE loading preferences. Our results suggest that these seemingly arbitrary processing characteristics are essential for establishing the self-incompatibility dominance hierarchy, as they enable a single sRNA precursor from a dominant allele to effectively repress multiple recessive alleles, thus providing a unique example of how small RNAs mediate gene silencing within a highly complex regulatory network.
The small GTPase RAS is a signalling hub activating multiple pathways, which may respond differently to a constitutively active RAS mutation. We explored this issue in fission yeast, where RAS-mediated pheromone signalli...The small GTPase RAS is a signalling hub activating multiple pathways, which may respond differently to a constitutively active RAS mutation. We explored this issue in fission yeast, where RAS-mediated pheromone signalling (PS) activates two downstream pathways: the MAPKSpk1 and Cdc42 pathways. We observed that the yeast RAS mutation ras1.G17V, an equivalent of the mammalian ras.G12V oncogenic mutation, causes prolonged Cdc42 activation, whereas MAPKSpk1 activation was transient and attenuated. To explain this observation, we generated a PS framework by conducting genetic epistasis analysis of PS mutants and biochemical analysis of two Ras1 effectors, Cdc42-GEFScd1 and MAPKKKByr2, each of which triggers activation of the Cdc42 and MAPKSpk1 pathways, respectively. Cdc42-GEFScd1 and MAPKKKByr2 directly interacted with Ras1 in vitro in a competitive manner, and overexpression of the Ras binding domain of either Cdc42-GEFScd1 or MAPKKKByr2 in cells inhibited both downstream pathways, confirming that Ras1 signalling branches into the MAPKSpk1 and Cdc42 pathways. In conjunction with the genetic epistasis analysis, we developed the PS framework-based mathematical model to test which network structures can explain the transient MAPKSpk1 activation profile. Incorporating a negative-feedback circuit acting on pheromone production or sensing enabled the model to quantitatively reproduce MAPKSpk1 dynamics in the wild type and 20 additional PS mutants. The predicted PS negative-feedback was experimentally confirmed by deleting Sxa2, the carboxypeptidase that degrades one of the mating pheromones, which led to hyperactivation of both MAPKSpk1 and Cdc42. Our study provides a holistic understanding of the fission yeast pheromone signalling network, explaining how RAS signalling propagates differently through two downstream pathways. Our PS mathematical model may serve as a valuable reference framework for analysing other RAS signalling systems.
The polarized architecture of neurons is intricately associated with the modulation of microtubule dynamics. Over the years, several microtubule-associated factors that regulate neuronal polarity have been identified. Ho...The polarized architecture of neurons is intricately associated with the modulation of microtubule dynamics. Over the years, several microtubule-associated factors that regulate neuronal polarity have been identified. However, the precise details of how microtubule arrangement and stability are established in axons and dendrites are not clearly understood. To uncover the relevant factors involved in the biological pathways governing microtubule regulation in neurons, we conducted a suppressor screen using the neuronal ectopic extension phenotype caused by the loss of the kinesin-13 family microtubule depolymerizing protein KLP-7 in C. elegans. Interestingly, apart from eleven variants of α (mec-12) and β (mec-7) tubulins, we isolated a variant of cytokinesis-associated protein, W02B8.2/citk-1, the suggested kinase-less orthologue of mammalian citron-rho interacting kinase (CIT). Little is known about the role of CIT in microtubule regulation in post-mitotic neurons. In this study, we found that the kinase-less worm orthologues of CIT, citk-1 and citk-2, redundantly modulate microtubule stability in the axon-like anterior process and maintain the population of plus-end-out microtubules in the dendrite-like posterior process of the PLM mechanosensory neurons in a cell-autonomous manner. In the absence of citk-1 and citk-2, PLM neurons exhibit variable morphological defects, including neurite growth and synaptic branch defects. Moreover, we find that CITK-1/2 work in the same genetic pathway as ASPM-1 (the worm homolog of mammalian ASPM (abnormal spindle-like microcephaly-associated protein)) to modulate plus-end dynamics of microtubules in PLM neurons. Our findings suggest that the cytokinesis-associated CITK-1/2 and ASPM-1 have non-mitotic roles in regulation of microtubules in differentiated PLM neurons.
Oocyte vitrification is indispensable in assisted reproduction, yet its link to compromised embryonic development remains mechanistically unresolved. Here, this study demonstrate through integrated transcriptome and tran...Oocyte vitrification is indispensable in assisted reproduction, yet its link to compromised embryonic development remains mechanistically unresolved. Here, this study demonstrate through integrated transcriptome and translatome analysis that vitrification disrupts maternal mRNA translation-sparing global transcriptional output-in mouse oocytes. This translational perturbation prominently suppresses genes encoding spliceosome components, including Phf5a, leading to persistent and widespread alternative splicing defects in subsequent 2-cell embryos. Importantly, aberrant splicing specifically depletes the functional full-length transcript of the essential zygotic genome activation (ZGA) regulator Crxos (Egam1) while elevating a truncated, non-functional variant (Egam1ΔEXON3). Functional analyses confirm that loss of Crxos in 2‑cell embryos not only compromises developmental progression but also reduces global transcriptional activity, likely via impaired RNA Pol II recruitment and elongation at ZGA genes. Together, this work delineates a linear pathological cascade triggered by oocyte vitrification, comprising maternal translational suppression, spliceosome impairment, Crxos aberrant splicing, impaired ZGA, and developmental compromise, thereby offering a mechanistic basis for refining cryopreservation protocols in reproductive medicine.
SKI-INTERACTING PROTEINS (SKIPs), primarily known as splicing factors, control gene expression at the post-transcriptional level in stress responses in plants. However, little is known about SKIPs in regulating plant dro...SKI-INTERACTING PROTEINS (SKIPs), primarily known as splicing factors, control gene expression at the post-transcriptional level in stress responses in plants. However, little is known about SKIPs in regulating plant drought stress at the transcriptional level, particularly in maize (Zea mays L.). Here, we discover that ZmSKIP enhances drought tolerance in maize. ZmSKIP transgenic plants were generated to study how ZmSKIP positively regulates drought tolerance. Overexpression of ZmSKIP promoted stomatal closure and reduced water loss, whereas the opposite effect was observed in skip-aa mutants. ZmSKIP directly binds to the "TAATA" motif in the promoter of B-cell lymphoma 2-associated athanogene 8 (ZmBAG8). bag8 mutants exhibit the decreased water loss and reduced stomatal aperture phenotype under drought stress. Additionally, ZmSKIP can be recruited by ZmBAG8 in stress granules (SGs) to decrease its protein abundance in the nucleus. Increased ZmBAG8 expression leads to larger stomatal aperture and normal plant growth. Under drought stress, the interaction between ZmSKIP and ZmBAG8 was abolished, while ZmSnRK2.3 phosphorylates ZmSKIP at Ser236 and Ser244 to enhances drought tolerance by strengthening the ability of ZmSKIP to suppress ZmBAG8 expression. Thus, our findings demonstrate that ZmSnRK2.3-mediated phosphorylation of ZmSKIP reduces ZmBAG8 expression and stomatal aperture, thereby enhancing drought tolerance in maize.
Abnormal placentation drives many pregnancy-related pathologies and poor fetal outcomes, but the underlying molecular causes are understudied. Here, we show that persistent replication stress due to mutations in the MCM2...Abnormal placentation drives many pregnancy-related pathologies and poor fetal outcomes, but the underlying molecular causes are understudied. Here, we show that persistent replication stress due to mutations in the MCM2-7 replicative helicase disrupts placentation and reduces embryo viability in mice. MCM-deficient embryos exhibited normal morphology, but their placentae had a drastically diminished junctional zone (JZ). Whereas cell proliferation in the labyrinth zone (LZ) remained unaffected, it was reduced in the JZ during development. MCM2-7 deficient trophoblast stem cells (TSCs) failed to maintain stemness, suggesting that replication stress affects the initial trophoblast progenitor pool in a manner that preferentially impacts the developing JZ. In contrast, pluripotency of mouse embryonic stem cells (ESCs) with MCM2-7 deficiency were not affected. Developing female mice deficient for FANCM, a protein involved in replication-associated DNA repair, also had placentae with a diminished JZ. These findings indicate that replication stress-induced genomic instability compromises embryo outcomes by impairing placentation.
Gaur M, Brooks MJ, Liang X
… +10 more, Jiang K, Kumari A, English MA, Cifani P, Panepinto MC, Nellissery J, Fariss RN, Campello L, Marchal C, Swaroop A
High aerobic glycolysis in retinal photoreceptors, as in cancer cells, is implicated in mitigating energy and metabolic demands. Lactate, a product of glycolysis, can exert epigenetic regulation through histone lactylati...High aerobic glycolysis in retinal photoreceptors, as in cancer cells, is implicated in mitigating energy and metabolic demands. Lactate, a product of glycolysis, can exert epigenetic regulation through histone lactylation in cancer. Here, we show that enhanced ATP production during mouse retinal development is achieved primarily through increase in glycolysis. Histone lactylation, especially H3K18La, parallels increased glycolysis and lactate levels in the developing retina. Multi-omics analyses, combined with confocal imaging, reveal the localization of H3K18La near H3K27Ac in the euchromatin at promoters of active retinal genes. In mouse retinal explants, glucose metabolism is associated with lactate levels as well as H3K18La and consequently gene expression. However, inhibition of glycolysis with 2-deoxyglucose (2-DG) reduces global H3K18La and H3K27Ac marks with somewhat distinct transcriptional changes. Evaluation of accessible chromatin at H3K18La-marked promoters uncovers an enrichment of GC-rich motifs for transcription factors of SP, KMT and KLF families, among others, indicating the specificity of H3K18La-mediated gene regulation. Our results indicate glycolysis/lactate/H3K18La as a potential axis for transcriptional response to changing metabolic conditions in the retina, especially photoreceptors.