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PubMed2026

The HOXA gene cluster: a critical regulator in bone-related disorders.

BACKGROUND: Skeletal homeostasis relies on the dynamic balance between bone formation and bone resorption. The disruption of this balance acts as the central pathological mechanism of multiple metabolic bone diseases including osteoporosis, and is closely correlated with the progression of various other bone-related disorders. As pivotal transcription factors regulating embryonic development and cell fate, the homeobox A (HOXA) gene family plays an essential role in skeletal physiological and pathological processes. METHODS: This review systematically summarizes recent research advances of the HOXA gene family in bone-related diseases, concludes the evolutionarily conserved regulatory patterns of HOXA members, and clarifies the molecular mechanisms by which HOXA genes mediate bone metabolic disorders and the occurrence as well as development of bone diseases. RESULTS: Accumulating evidence demonstrates that HOXA family members present complex functions and strong heterogeneity in bone-related diseases. They participate in the pathogenesis of bone diseases via three evolutionarily conserved regulatory manners: determining regional patterning, modulating signaling pathways, and integrating epigenetic and non-coding RNA (ncRNA) regulatory networks. CONCLUSION: Further exploring the underlying mechanisms of the HOXA family in bone-related diseases provides novel insights into the pathogenesis of bone disorders. Meanwhile, it also supplies solid theoretical basis and potential therapeutic targets for the development of novel HOXA-targeted therapeutic strategies against bone diseases.

Humans↗

PubMed2025

Genetic and chromatin regulation of Pvt1 monoallelic expression.

While most genes are equivalently expressed on both alleles, genes with random monoallelic expression (RME) stably maintain expression from only one allele, but the mechanisms and consequences of RME remain unclear. We performed allele-specific RNA sequencing (RNA-seq) on ∼100 F1 hybrid neural progenitor cell (NPC) clonal lines to reveal the extent of autosomal RME (aRME). Of the 287 aRME genes, Pvt1, an oncogenic long non-coding RNA, is an aRME with a genetic bias. In the absence of genetic differences, Pvt1 undergoes balanced aRME. Pvt1 monoallelic expression is maintained by allele-specific active and repressive histone modifications, opposed to DNA methylation. Additionally, we provide a two-step mechanism for the initiation of aRME and demonstrate that Pvt1 monoallelic expression results in a growth phenotype due to the interplay with Myc. These findings provide insight into how genetic differences can skew a stochastic process, resulting in monoallelic expression with a phenotypic consequence in early development.

Chromatin↗

PubMed2026

Single-cell multiomics reveals exosome-mediated reprogramming and clonotypic remodeling of T cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and immunogenic subtype lacking targeted therapies. While tumor-derived exosomes are known to modulate immune function, their direct impact on human T cell plasticity and antigen specificity remains poorly defined. Here, we conducted a comprehensive single-cell multiomic analysis of primary human T cells exposed to exosomes derived from 17 genomically diverse TNBC cell lines and 35 patient samples. Integrating single-cell RNA-seq, V(D)J sequencing, non-coding RNA profiling, bulk and single-cell cytokine analyses, we uncovered conserved and subtype-specific immunomodulatory programs induced by TNBC exosomes. Exosome-treated T cells displayed skewing toward regulatory and dysfunctional phenotypes, including Th17-like, Treg, and PD-1⁺/PD-L1⁺ Tfh cells. Functional profiling revealed suppression of early activation markers and cytokine responses, alongside selective preservation of cytotoxic features in γδ T and NKT subsets. Transcriptomic and miRNA network analyses demonstrated widespread downregulation of immune effector genes (e.g., HBEGF and TNFSF9) mediated by exosome-delivered regulatory miRNAs (has-miR-98-5p). Notably, exosome-stimulated T cells displayed distinct clonotypic expansions, characterized by the emergence of five tumor-specific γδ TCR clonotypes and 30 unique αβ TCR CDR3 sequences that were absent in mock-treated controls, underscoring the role of exosomes in shaping TCR repertoire dynamics.

Humans↗

PubMed2023

Non-coding regions of nuclear-DNA-encoded mitochondrial genes and intergenic sequences are targeted by autoantibodies in breast cancer.

Autoantibodies against mitochondrial-derived antigens play a key role in chronic tissue inflammation in autoimmune disorders and cancers. Here, we identify autoreactive nuclear genomic DNA (nDNA)-encoded mitochondrial gene products (GAPDH, PKM2, GSTP1, SPATA5, MFF, TSPOAP1, PHB2, COA4, and HAGH) recognized by breast cancer (BC) patients' sera as nonself, supporting a direct relationship of mitochondrial autoimmunity to breast carcinogenesis. Autoreactivity of multiple nDNA-encoded mitochondrial gene products was mapped to protein-coding regions, 3' untranslated regions (UTRs), as well as introns. In addition, autoantibodies in BC sera targeted intergenic sequences that may be parts of long non-coding RNA (lncRNA) genes, including LINC02381 and other putative lncRNA neighbors of the protein-coding genes ERCC4, CXCL13, SOX3, PCDH1, EDDM3B, and GRB2. Increasing evidence indicates that lncRNAs play a key role in carcinogenesis. Consistent with this, our findings suggest that lncRNAs, as well as mRNAs of nDNA-encoded mitochondrial genes, mechanistically contribute to BC progression. This work supports a new paradigm of breast carcinogenesis based on a globally dysfunctional genome with altered function of multiple mitochondrial and non-mitochondrial oncogenic pathways caused by the effects of autoreactivity-induced dysregulation of multiple genes and their products. This autoimmunity-based model of carcinogenesis will open novel avenues for BC treatment.

autoimmunity↗

PubMed2026

Unraveling the c-Myc-CASC19/HDAC1-NPM1 epigenetic axis: A novel regulatory circuitry and therapeutic target in gastric carcinogenesis.

Mounting evidence implicates long non-coding RNA cancer susceptibility candidate 19 (CASC19) in the pathogenesis of diverse malignancies. However, its functional role and molecular mechanisms in gastric cancer (GC) remain elusive. Herein, we identified a novel 717-bp transcript isoform of CASC19 in GC cells. This study aimed to delineate the biological functions and underlying mechanisms of this novel CASC19 transcript in GC pathogenesis. CASC19 was significantly upregulated in GC tissues and cell lines, correlating with adverse clinicopathological features and poor prognosis in GC patients. Functional investigations demonstrated that CASC19 overexpression potentiated GC cell proliferation, metastasis, and epithelial-mesenchymal transition, whereas CASC19 knockdown attenuated these malignant phenotypes and suppressed tumorigenesis in xenograft models. Mechanistically, CASC19 functioned as a molecular scaffold by recruiting histone deacetylase 1 (HDAC1) to the nucleophosmin 1 (NPM1) promoter. This recruitment sustained H3K27 deacetylation, thereby transcriptionally repressing NPM1 promoter activity and accelerating gastric carcinogenesis. Crucially, Depletion of HDAC1 or NPM1 partial rescued CASC19-mediated oncogenic effects. Intriguingly, the transcription factor c-Myc was found to transcriptionally activate CASC19 through direct binding to its promoter region. Collectively, our findings indicate that the c-Myc-CASC19/HDAC1-NPM1 axis acts as a potential prognostic biomarker candidate for GC and may represent a therapeutic vulnerability worthy of future investigation.

Humans↗

PubMed2026

Landscape of retron diversity across the SPIRE microbial metagenome resource reveals candidate novel type XI-like lineages.

Retrons are bacterial genetic elements encoding a specialized reverse transcriptase (RT) that synthesizes multicopy single-stranded DNA and are increasingly recognized as components of bacterial anti-phage defense systems. However, their diversity and ecological distribution across large-scale genomic resources remain poorly characterized. Here, we surveyed retron RTs across the SPIRE representative metagenome collection, a non-redundant, species-level data set spanning diverse microbial habitats. Using a curated panel of type-specific hidden Markov models, we identified retrons representing all canonical types together with additional divergent lineages. Retron distribution showed strong taxonomic and ecological structuring, with some groups restricted to specific bacterial phyla, whereas others were broadly distributed across environmental categories. Systematic novelty assessment identified two candidate type XI-like lineages, TXI_C2like and TXI_noncan_h, characterized by protease-independent architectures and distinct accessory modules associated with WYL- and DnaB_C-containing proteins, respectively. De novo covariance-based analyses further identified candidate msr/msd-like non-coding RNA structures in both lineages, supporting conservation of the canonical RT-ncRNA organizational framework despite extensive sequence divergence. Together, these findings expand the known diversity of retron systems and identify type XI-like retrons as a dynamic and previously underexplored evolutionary group.IMPORTANCERetrons are bacterial genetic elements that are increasingly exploited as programmable tools for genome editing, molecular recording, and biosensing in addition to their natural role in anti-phage defense. Despite this growing biotechnological interest, the true diversity of retrons across the bacterial world has remained largely unmapped. By mining a resource of over 100,000 processed microbial metagenomes, we uncovered thousands of retron sequences spanning known types as well as previously unrecognized lineages and found that their distribution is strongly shaped by both bacterial taxonomy and ecological niche. Among these, we identified two candidate new lineages related to type XI retrons that lack the protease domain typical of this group but instead carry distinct accessory proteins, expanding the known architectural diversity of these systems. These findings broaden the catalog of retron diversity available for functional characterization and biotechnological engineering and provide a framework for prioritizing candidate lineages for future experimental validation.

effectors↗

PubMed2026

Beyond Canonical Neoantigens: Emerging Technologies for Identification of Noncanonical Antigens and Implications for Personalized Cancer Vaccines.

Over the past decade, advances in sequencing technologies and computational pipelines enabled the development of personalized cancer vaccines (PCVs). Current PCV strategies primarily target cancer neoantigens generated by non-synonymous DNA mutations, which can result in altered amino acid sequences capable of eliciting tumor-specific immune responses. More recently, a distinct class of tumor-specific antigens (TSA), termed noncanonical or cryptic antigens, has emerged as an additional source of immunogenic targets. Unlike canonical neoantigens, noncanonical antigens typically cannot be identified by tumor/normal whole-exome sequencing, as they do not arise from classical DNA mutations. Instead, they are often associated with less well recognized and/or aberrant processes in the pathways from DNA to human leukocyte antigen (HLA)-presented peptides. Examples include transposable elements, circular RNA, translation of alternative open reading frames and/or long non-coding RNA, among others. Emerging evidence suggests that noncanonical antigens represent a substantial portion of the tumor-specific immunopeptidome and, similar to canonical neoantigens, are absent during thymic selection and can evade central tolerance and elicit T cell responses. Technological advances have increasingly facilitated the identification of noncanonical antigens. Long-read RNA sequencing reveals noncanonical transcripts by improving transcriptome assembly, while ribosome profiling provides genome-wide maps of actively translated regions, facilitating the discovery of peptides from aberrant translation events. Specialized molecular approaches enable enrichment and sequencing of circular RNAs, and immunopeptidomics using mass spectrometry allows for direct characterization of HLA-presented peptides. Together, these technological advances have led to an increasing interest in prioritizing and targeting noncanonical antigens in the next generation of PCVs. This review provides an overview of the diverse origins of TSAs beyond classical neoantigens and discusses emerging approaches that may enable the integration of these antigens in future clinical trials.

circular RNA↗

PubMed2026

Deletion of the MALAT1 RNA 3' end promotes transcript decay and inhibits proliferation in gastric and breast cancer cells.

The long non-coding RNA MALAT1 is a conserved oncogenic driver whose function relies on a 3' triple-helix motif. While its biochemistry is well-characterized in vitro, the endogenous requirement for this motif in regulating the stability of the transcript and other genes residing in its locus remains unclear. In this study, we employed a dual-sgRNA CRISPR-Cas9 approach to systematically excise triple-helix-forming sequences from the native MALAT1 locus in gastric (AGS) and breast (MCF7) cancer cells. Our findings demonstrate that the 3' end strongly contributes to MALAT1 stability. Perturbations ranging from genomic deletions to a single-base changes trigger transcript collapse and rapid exonucleolytic decay, while the biogenesis of the small RNA mascRNA (a byproduct of MALAT1, also involved in cancer) remains decoupled and unaffected. In cellulo, DMS probing reveals that edited transcripts retain structural complexity in the 3' region. Phenotypically, structural disruption of the 3' end significantly impairs proliferation of both cancer cellular models. These results identify the 3' triple-helix as a determinant of MALAT1 stability and provide endogenous validation for its role in the analyzed AGS and MCF7 cells.

Cancer↗

PubMed2026

The dark genome in cardiovascular medicine.

Only ∼1%-2% of the human genome directly codes for proteins. The remainder consists of non-coding DNA, often referred to as the 'dark genome'. This includes regulatory elements, transposable and repetitive sequences, structural genomic features, pseudogenes, intronic and intergenic regions, and non-coding RNA (ncRNA) genes. These components are increasingly recognized as major regulators of gene expression, cell identity, and disease susceptibility. Currently, dark genome elements, particularly ncRNAs are increasingly recognized as important regulators of cardiovascular health and disease. Advances in genome analysis technologies have greatly improved our understanding of these non-coding regions and revealed clearer connections between the dark genome and cardiovascular traits. This review highlights major parts of the dark genome involved in cardiovascular disease, with emphasis on those for which mechanistic understanding and translational relevance are beginning to emerge. As mechanistic insight into individual and collective components of the dark genome advances, it increasingly enables the development of new opportunities for targeted therapeutics for cardiovascular prevention and disease management.

Humans↗

PubMed2026

The chromatin reader ZMYND8 recruits the NuRD component GATAD2A through its MYND domain to regulate MAPT213 long noncoding RNA transcription.

The zinc finger MYND-type containing eight protein (ZMYND8) is a chromatin reader that regulates neuronal gene expression by controlling the microtubule-associated protein tau (MAPT) locus. Here, we investigate how ZMYND8 regulates expression of the long non-coding RNA MAPT213 through its interaction with GATA zinc finger domain containing 2A (GATAD2A), a component of the Nucleosome Remodelling and Deacetylase complex. ZMYND8 exhibits opposite regulatory effects on protein-coding MAPT and non-coding MAPT213 transcripts in a manner dependent on its MYND domain, promoting MAPT expression while suppressing MAPT213 levels. Chromatin immunoprecipitation experiments demonstrated that ZMYND8 specifically recruits GATAD2A to the MAPT213 internal regulatory region, establishing a direct link between protein binding and transcriptional control. We determined the crystal structure of the ZMYND8 coiled-coil MYND domain at high resolution, revealing a homodimeric architecture. The MYND domain specifically recognizes GATAD2A through direct interaction with proline-rich motifs in GATAD2A's central region. Structure-function analysis identified critical binding interface residues, while quantitative measurements revealed moderate-affinity interactions enhanced through multivalent binding mechanisms. These findings establish the molecular basis for ZMYND8-mediated recruitment of chromatin remodeling complexes to specific genomic loci and provide a structural framework for understanding transcriptional regulation of MAPT213.

Humans↗

PubMed2026

Cleavage region organizes the structural architecture of the SINE-derived B2 repressive ribozyme.

The SINE-encoded B2 retrotransposon is an RNA Polymerase III (POL-III)-derived transcript whose expression is substantially upregulated during various cellular stress responses. Beyond retrotransposition, the B2 non-coding RNA can directly bind and repress the activity of RNA Polymerase II (POL-II), leading to a significant downregulation of transcripts during stress. Notably, our recent findings have shown that B2 is a self-cleaving ribozyme whose activity can be induced by interactions with chromatin-modifying factors through non-canonical epigenetic mechanisms that co-regulate its function across distinct chromatin-binding target loci. Here, by integrating RNA chemical probing, small-angle X-ray scattering, and 3D motif modeling, we determine structural ensemble-to-function relations for the B2 SINE ribozyme RNA. Genetic perturbations of the RNA suggest that the B2 SINE ribozyme has a well-defined secondary and dynamic tertiary structure that depends on the integrity of the critical region, which confers ribozymatic activity and repressive extent by POL-II. Using an RNA engineering approach, we examine the effects of point mutations, deletions of the main cleavage site, and deletions of the cleavage domain on the structural ensemble of the RNA. Combining this approach with in vitro and in vivo functional perturbation methods highlights the relationships between structural ensembles and various biologically relevant functional outcomes.

RNA, Catalytic↗

PubMed2025

Scalable single-cell total RNA-seq reveals non-coding programs in immunity, infection, and brain development.

Non-coding RNAs represent a widespread and diverse layer of post-transcriptional regulation across cell types and states, yet much of their diversity remains uncharted at single-cell resolution. This gap stems from the limitations of widely used single-cell RNA-sequencing protocols, which focus on polyadenylated transcripts and miss many short or non-polyadenylated RNAs. Here, we adapted single-cell RNA-sequencing on the 10x Genomics platform to capture a broad complement of coding and non-coding RNAs-including miRNAs, tRNAs, lncRNAs, histone RNAs, and non-adenylated viral transcripts. This approach enabled the discovery of rich, dynamic non-coding RNA programs across immune cells, virally infected hepatocytes, and the developing human brain. In dengue virus-infected hepatocytes, we detect non-adenylated viral transcripts and distinguish active from transcriptionally quiescent infected states, each with distinct host regulatory signatures. In brain tissue, we identify biotype-specific, cell-type-restricted non-coding RNAs, including miRNAs whose expression anticorrelates with predicted targets, consistent with post-transcriptional regulatory relationships. We show that MIR137, one of the strongest GWAS loci associated with schizophrenia and intellectual disability, is expressed specifically in Cajal-Retzius cells, an early-born but transient population that guides subsequent cortical neuron migration. These findings demonstrate the importance of non-coding RNAs in defining cell identity and state, and show how expanded transcriptome coverage can reveal additional layers of gene control-now accessible through practical and scalable single-cell profiling.

Journal Article↗

PubMed2025

RNA-RNA interactions coordinate GABA metabolism and signaling.

Production, signaling, and degradation of the inhibitory neurotransmitter GABA requires tight regulation for proper nervous system function, yet the gene regulatory mechanisms underlying this control remain poorly understood. Here, we identify a post-transcriptional mechanism that coordinates expression of the GABA synthetase Gad1 with its vesicular transporter VGAT in Drosophila. While Gad1 is transcribed specifically in GABAergic neurons, VGAT mRNA is transcribed broadly across the nervous system, but is selectively translated in GABAergic neurons. We show that this specificity depends on CG14989, a putative long non-coding RNA located adjacent to the Gad1 gene locus that shares its GABAergic expression pattern. CG14989 RNA contains sequences complementary to three predicted miR-7 sites in the VGAT 3'UTR, and ectopic expression experiments revealed that it is sufficient for VGAT translation in non-GABAergic neurons, consistent with antagonism of miR-7-mediated repression. Furthermore, complementary regions to CG14989 are present in multiple other genes related to metabolism and signaling of GABA, suggesting a broader role for this mechanism. Together, our findings suggest that CG14989 functions as a regulatory hub that coordinates the molecular identity of GABAergic neurons.

Journal Article↗

PubMed2026

Dual regulation of the receptor-like kinase BIR1 involves site-directed transcript cleavage and 5'-leader-mediated translational control.

In Arabidopsis, BRASSINOSTEROID INSENSITIVE1-ASSOCIATED RECEPTOR KINASE 1 (BAK1)-INTERACTING RECEPTOR-LIKE KINASE 1 (BIR1) is a negative regulator of plant immunity and cell death. BIR1 was earlier described as a target of epigenetic and post-transcriptional degradation. During virus infections, degradome analysis of BIR1 transcripts mapped predominant mRNA cleavage sites at the 5'-untranslated leader region (site A) and the protein-coding sequence (sites B and C). Here, we identified another virus-associated cleavage site (D) within the BIR1 coding region and investigated the contribution of site-directed mRNA cleavage to BIR1 regulation. Mutations at B, C, and D sites enhanced mRNA stability by impairing transcript cleavage, resulting in increased BIR1 mRNA and protein accumulation. This regulation is disrupted in RNA silencing mutants, supporting a model of cis-directed small interfering RNA (siRNA)-mediated degradation. We next demonstrate that virus infection reduces BIR1 translation in Arabidopsis. Furthermore, our data reveal a repressive role for the 5'-leader in regulating BIR1 translation, potentially mediated by upstream open reading frames (uORFs) and a virus-responsive long non-coding RNA (lncRNA) derived from the natural antisense At4g39838 locus. Together, these findings reveal a multilayered regulatory mechanism that integrates sRNA-mediated cleavage with translational control, with broader implications for the fine-tuning of stress-responsive gene expression during infection.

Arabidopsis↗

PubMed2025

Nfe2l1 dysfunction alters Parkinson's disease-related gene expression and impairs neuronal differentiation under ubiquitin stress in neuronal differentiated P19 Cells.

Proteostasis is essential for neuronal health, and its disruption is implicated in neurodegenerative diseases such as Parkinson's disease (PD). Nfe2l1, a key regulator of proteostasis and ubiquitination, plays a significant role in neuronal health, yet its molecular functions in neuronal cells remain unclear. Our study investigates the role of Nfe2l1 in RA-induced neuronal differentiation of P19 cells under proteasome inhibition. This condition significantly increased Nfe2l1 expression at both protein and RNA levels in wild-type and differentiated cells. In differentiated cells under proteasome inhibition, RNA sequencing revealed an enrichment of neurodegenerative pathways, particularly those associated with PD. Proteasome inhibition led to the upregulation of several PD-related genes, including Atf6, Camk2d, and Sod1. However, Nfe2l1 knockdown in differentiated cells significantly reduced the expression of these genes, highlighting the role of Nfe2l1 in the regulation of PD-related pathways. Knockdown of Nfe2l1 also decreased Neat1, a long non-coding RNA associated with PD pathology, and downregulated the neuronal marker Map2, indicating impaired neuronal differentiation. Furthermore, Nfe2l1 knockdown increased ubiquitination under proteasome inhibition, emphasizing its role in protein degradation and neuronal homeostasis under stress. These findings highlight Nfe2l1 as a critical regulator in neuronal cells and reveal its potential role in maintaining proteostasis and involvement in neurodegenerative disease mechanisms, such as PD.

Parkinson Disease↗

PubMed2025

Chromosome-level genome assembly of Nothapodytes nimmoniana.

Nothapodytes nimmoniana is a plant species belonging to the genus Nothapodytes in the family Icacinaceae. This species holds significant medicinal value due to its camptothecin content. In this study, we present the first chromosome-level genome assembly of N. nimmoniana constructed using NGS, Hi-C, and HiFi sequencing technologies. The assembled genome spans 3.53 Gb across 14 chromosomes, with an N50 length of 248.74 Mb. Genome annotation revealed that repetitive sequences constitute 80.82% of the genome size, and 83,269 protein-coding genes were predicted. Additionally, 4,360,538 bp of non-coding RNA were annotated. This genomic resource provides a foundation for further investigation into camptothecin biosynthesis pathways and plant phylogeny in N. nimmoniana.

Genome, Plant↗

PubMed2026

Nuclear DNA of plastid origin (NUPTs), neglected driver of genome variation and evolutionary innovation.

Plant nuclear genomes contain a variable, though typically minor, fraction of DNA sequences of plastid origin known as NUPTs. Unlike the massive transfer of DNA and genes from the proto-organelle genome to the nucleus that occurred during the endosymbiotic event that gave rise to plastids, the formation of NUPTs is an ongoing process that does not imply concomitant DNA loss. Although NUPTs are generally considered to be potentially deleterious insertions that are continuously generated and rapidly eliminated at near-constant turnover rates, accumulating evidence reveals alternative evolutionary trajectories. In this review, we discuss recent findings that highlight the episodic formation of NUPTs, their subsequent proliferation, and their eventual long-term fixation within the nuclear genome. We also explore their non-random spatial association with specific genomic elements. NUPTs show preferential overlap with specific superfamilies of transposable elements, which may facilitate their proliferation and dispersal throughout the nuclear genome. Regarding protein-coding genes, the contribution of NUPTs varies among species. In contrast, NUPTs are found to be consistently enriched among certain classes of non-coding RNA genes, notably rRNA, tRNA, and specific regulatory RNA families, suggesting that they are involved in the evolution of gene regulation and translational machinery. Overall, these findings underscore the unexpected complexity of the mechanisms underlying NUPT formation and support the idea that they are a significant source of genome variation and evolutionary innovation. Further research is necessary to fully elucidate the mechanisms underlying NUPT formation, as well as to determine their potential adaptive significance in plant genome evolution.

Plastids↗

PubMed2024

Complementation testing identifies genes mediating effects at quantitative trait loci underlying fear-related behavior.

Knowing the genes involved in quantitative traits provides an entry point to understanding the biological bases of behavior, but there are very few examples where the pathway from genetic locus to behavioral change is known. To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six quantitative trait loci (QTLs) by quantitative complementation, and identified six genes. Four genes, Lamp, Ptprd, Nptx2, and Sh3gl, have known roles in synapse function; the fifth, Psip1, was not previously implicated in behavior; and the sixth is a long non-coding RNA, 4933413L06Rik, of unknown function. Variation in transcriptome and epigenetic modalities occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results relieve a bottleneck in using genetic mapping of QTLs to uncover biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.

Animals↗