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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

Epi-Allele elicits compensatory expression of the non-targeted allele and prevents haploinsufficiency in dominant genetic diseases.

Epigenetic regulation may underlie asymmetric allelic expression of many genes during development and disease pathogenesis. Allele-specific epigenetic modification could provide an efficient therapy for dominant genetic diseases due to heterozygous mutations. We developed an allele-specific epigenetic editing method ("Epi-Allele") for silencing pathogenic alleles and found surprisingly elevated expression of the non-targeted alleles, leaving total gene expression unchanged. Genome-wide screening revealed that such compensated allelic expression represents a common phenomenon, suggesting that the Epi-Allele approach could avoid the haploinsufficiency induced by current allele-specific silencing therapies. This notion was validated by allele-specific epigenetic remodeling of Myh6 and MYH7 genes in ameliorating cardiac phenotypes in a hypertrophic cardiomyopathy (HCM) mouse model and HCM patient iPSC-derived cardiomyocytes, respectively. Thus, Epi-Allele offers an allele-specific haploinsufficiency-free therapeutic approach for treating dominant genetic diseases.

DNA methylation↗
PubMed2025

Targeting hepatocyte-specific SLC2A8 blocks hepatic steatosis and dissociates TCA cycle flux inhibition from glutamine anaplerosis.

BACKGROUND: Excess TCA cycle and glutamine anaplerosis are hallmarks of metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Blocking glutamine metabolism attenuates metabolic dysfunction-associated steatohepatitis. However, inhibiting TCA cycle flux by blocking plasma membrane carbohydrate transport is limited by the ubiquitous tissue distribution, function, and homology among the SLC2A family of facilitative carbohydrate transporters, and the potential for carbohydrate blockade to invoke or exacerbate glutamine anaplerosis. Here, we quantify alterations in hepatocyte carbon flux, define the broader metabolic consequences of hepatocyte-specific GLUT8/SLC2A8 inhibition, and delineate the antisteatotic efficacy of a novel small-molecule GLUT8-selective inhibitor. METHODS: We generated mice with floxed SLC2A8 alleles and expressed hepatocyte-specific Cre by breeding these mice with albumin-Cre transgenic mice, or by administering AAV8 encoding hepatocyte-specific iCre. We performed stable-isotope glucose, fructose, and glutamine metabolic labeling in isolated GLUT8WT and GLUT8LKO hepatocytes and performed metabolic phenotyping in lean and diet-induced obese GLUT8WT and GLUT8LKO mice. Finally, we performed high-throughput screening to identify a GLUT8-selective inhibitor, which we characterized using in vitro models of triglyceride accumulation. RESULTS: Hepatocyte-specific SLC2A8 deletion reduced diet-induced hepatic and peripheral fat accumulation and increased thermogenesis during ZT12-24 (eg, the dark phase). It also disrupted TCA cycle flux without inducing compensatory glutamine utilization. High-throughput screening identified a small-molecule, GLUT8-selective inhibitor, P20, which blocked hepatocyte TG accumulation and inflammation in in vitro steatotic and inflammatory models. CONCLUSIONS: Deleting the hepatocyte carbohydrate transporter GLUT8 suppresses TCA cycle flux without inducing compensatory glutamine anaplerosis. The net effect of this is liver protection against multiple forms of dietary insult. Given that selective pharmacological GLUT8 inhibition is feasible, GLUT8 may be a viable target to abate metabolic dysfunction-associated steatohepatitis and other complications of obesity.

Animals↗
PubMed2026

scSNViz: visualization and analysis of cell-specific expressed SNVs.

MOTIVATION: Accurately characterizing expressed genetic variation at the single-cell level is essential for understanding transcriptional heterogeneity, allelic regulation, and mutational dynamics within complex tissues. However, few tools enable comprehensive visualization and quantitative analysis of expressed variants across individual cells. RESULTS: scSNViz is an R package for the exploration, quantification, and visualization of expressed single-nucleotide variants (SNVs) from cell-barcoded single-cell RNA sequencing (scRNA-seq) data. The software supports estimation of variant allele fractions, clustering of SNV expression profiles, and 2D and 3D visualization of individual SNVs or user-defined SNV groups. Beyond visualization, scSNViz facilitates investigation of cell-, cluster-, or lineage-specific variant expression patterns, as well as allelic dynamics including imprinting, random allele inactivation, and transcriptional bursting. It interoperates seamlessly with established single-cell frameworks-Seurat for clustering, Slingshot for trajectory inference, scType for cell-type annotation, and CopyKat for copy-number profiling-enabling integrative multi-omic analyses of expressed variation. AVAILABILITY AND IMPLEMENTATION: scSNViz is implemented in R and freely available at https://github.com/HorvathLab/scSNViz (DOI: 10.5281/zenodo.17307516). The package includes comprehensive documentation and example workflows designed for users with limited bioinformatics experience.

Software↗
PubMed2026

SNP-derived CpG variation and DNA methylation linking genetic susceptibility to metabolic disease.

DNA methylation at CpG dinucleotides represents a key epigenetic mechanism linking genetic variation to gene regulation in complex human diseases. Single-nucleotide polymorphisms (SNPs) that create or disrupt CpG sites can alter local DNA methylation and transcriptional activity, thereby influencing disease susceptibility. These CpG-modifying variants provide a functional interface between inherited genetic variation and epigenetic regulation in complex metabolic disorders. This review summarizes current evidence on SNP-derived CpG variation and its role in allele-specific DNA methylation and gene regulation in metabolically relevant tissues. By integrating findings from genome-wide association studies, epigenome-wide association studies, and multi-omics research, this review provides a mechanistic framework explaining how CpG-modifying polymorphisms influence adipogenesis, pancreatic β-cell function, inflammation, and glucose metabolism. Special emphasis is placed on South Asian populations, who exhibit early β-cell dysfunction and increased visceral adiposity. Many CpG-modifying variants act as methylation quantitative trait loci (meQTLs), influencing allele-specific methylation and gene expression. Understanding SNP-CpG-methylation interactions may improve functional interpretation of disease-associated genetic variants, enhance biomarker discovery, and support precision medicine strategies for metabolic disease.

Humans↗
PubMed2025

Integrative Genomic, Transcriptomic and Epigenomic Analysis Reveals cis-regulatory Contributions to High-altitude Adaptation in Tibetan Pigs.

The Qinghai-Tibet Plateau, characterized by its extreme environmental conditions, presents significant challenges to life, making it an ideal region for studying adaptation and evolution. Tibetan pigs, known for their high genetic diversity and exceptional adaptability to high altitudes, serve as excellent models for investigating high-altitude adaptation. While previous studies have extensively identified genetic determinants associated with high-altitude adaptation, the molecular mechanisms, particularly cis-regulatory patterns, remain poorly understood. Here, we conducted a selective sweep analysis using 484 genomes from Chinese and Western pig breeds across various altitudes, revealing 38.56 Mb of genomic regions under selection in Tibetan pigs. Enrichment analysis identified the lung as the primary functional tissue involved in high-altitude adaptation, supported by tissue-specific transcriptional and regulatory patterns observed between Tibetan and Meishan pigs (low altitude). By integrating genomic, RNA-seq, ATAC-seq, and H3K27ac HiChIP data, we constructed comprehensive enhancer-promoter regulatory maps of candidate genes and pinpointed promising genetic determinants associated with high-altitude adaptation, including SNPs in EPAS1, KLF13, SPRED1, and CFD. These loci were predicted to influence chromatin accessibility and the interactions of regulatory elements, with altered binding strength of relevant transcription factors. Further in vitro experiments confirmed that these loci function as allele-specific enhancers, modulating the expression of target genes. Our findings elucidate the regulatory basis of high-altitude adaptation in Tibetan pigs and provide valuable insights for exploring hypoxia-related diseases in livestock and humans.

Animals↗
PubMed2026

Allele-specific chromatin architecture shapes imprinted domains and coordinates a distal enhancer and antisense transcription at the mouse Mest-Copg2 domain.

Genomic imprinting results in parent-of-origin-dependent gene expression, but how three-dimensional genome organization contributes to imprinted gene regulation remains unclear. Using Capture Hi-C in mouse cortex and primary cortical neurons, we identified parental allele-specific chromatin architectures across multiple imprinted domains. These architectures largely originate from imprinting control regions and correlate with DNA methylation-sensitive CTCF binding. Active and inactive alleles of imprinted genes show distinct promoter interaction profiles and differential engagement with distal regulatory elements in both contact frequency and the epigenetic state of distal regions. A CRISPR interference screen identified a distal enhancer that regulates Mest-Copg2 imprinted expression through allele-specific chromatin interactions. In neurons, this enhancer activates Copg2 on the maternal allele, whereas on the paternal allele it drives Mest isoforms transcribed antisense to Copg2 and contributes to Copg2 repression. In summary, we show that allele-specific chromatin architecture coordinates maternal enhancer activity and paternal antisense transcription to control imprinted expression in neurons.

Animals↗
PubMed2026

Disruption of CTCF binding by germline non-coding variants in CDKN2B suppress CDKN2A expression and predispose to melanoma.

Some melanoma-prone families linked to the 9p21 locus, harboring the established susceptibility gene CDKN2A, lack pathogenic protein-coding variants. Using whole-exome and targeted sequencing, we identified three rare single-nucleotide variants in two melanoma-prone families and one sporadic melanoma case. Variants map to a conserved CTCF-bound region within the first intron of CDKN2B that physically interacts with CDKN2A. Analysis of UK Biobank showed significant enrichment of variants in this region in melanoma cases. Variants result in diminished CTCF binding in vitro. CTCF ChIP-seq in fibroblasts from the carriers of the largest family demonstrated loss of CTCF binding, accompanied by weakened promoter interactions and allele-specific reduction of CDKN2A p16 transcript expression from the variant haplotype. CRISPR-based perturbation of this region and editing of the large family variant into melanocytes resulted in reduced expression of p14 and p16 CDKN2A transcripts. These findings suggest that non-coding regulatory variants function as high-penetrance susceptibility alleles in melanoma families by altering CDKN2A function.

Journal Article↗
PubMed2016

Immunodominant Dengue Virus-Specific CD8+ T Cell Responses Are Associated with a Memory PD-1+ Phenotype.

UNLABELLED: Dengue disease is a large public health problem that mainly afflicts tropical and subtropical regions. Understanding of the correlates of protection against dengue virus (DENV) is poor and hinders the development of a successful human vaccine. The present study aims to define DENV-specific CD8(+)T cell responses in general and those of HLA alleles associated with dominant responses in particular. In human blood donors in Nicaragua, we observed a striking dominance of HLA B-restricted responses in general and of the allele B*35:01 in particular. Comparing these patterns to those in the general population of Sri Lanka, we found a strong correlation between restriction of the HLA allele and the breadth and magnitude of CD8(+)T cell responses, suggesting that HLA genes profoundly influence the nature of responses. The majority of gamma interferon (IFN-γ) responses were associated with effector memory phenotypes, which were also detected in non-B*35:01-expressing T cells. However, only the B*35:01 DENV-specific T cells were associated with marked expression of the programmed death 1 protein (PD-1). These cells did not coexpress other inhibitory receptors and were able to proliferate in response to DENV-specific stimulation. Thus, the expression of particular HLA class I alleles is a defining characteristic influencing the magnitude and breadth of CD8 responses, and a distinct, highly differentiated phenotype is specifically associated with dominant CD8(+)T cells. These results are of relevance for both vaccine design and the identification of robust correlates of protection in natural immunity. IMPORTANCE: Dengue is an increasingly significant public health problem as its mosquito vectors spread over greater areas; no vaccines against the virus have yet been approved. An important step toward vaccine development is defining protective immune responses; toward that end, we here characterize the phenotype of the immunodominant T cell responses. These DENV-reactive T cells express high levels of the receptor programmed death 1 protein (PD-1), while those from disease-susceptible alleles do not. Not only does this represent a possible correlate of immunodominance, but it raises the hypothesis that PD-1 might be a regulator that prevents excessive damage while preserving antiviral function. Further, as this study employs distinct populations (Nicaraguan and Sri Lankan donors), we also confirmed that this pattern holds despite geographic and ethnic differences. This finding indicates that HLA type is the major determinant in shaping T cell responses.

Alleles↗
PubMed2026

Haplotype-resolved 3D genome maps reveal RNAPII-mediated allelic regulation in hybrid rice.

To understand how the two parental genomes coordinate transcription in hybrids, chromatin architecture must be resolved at the haplotype level. Here, using phased Bridge-Linker Hi-C, we reconstructed a haplotype-resolved three-dimensional (3D) genome of the elite hybrid rice (Oryza sativa) line Shanyou 63 (SY63). We identified extensive allele-specific chromatin conformations. Furthermore, we generated allele-resolved RNAPII ChIA-PET maps and phased transcriptomes to explore how chromatin interactions contribute to allelic regulation. Although maternal and paternal homologs share broadly similar chromatin features, we detected widespread haplotype-biased RNAPII binding and chromatin looping at high resolution. These allele-specific RNAPII-mediated contacts were significantly associated with biased expression. Stronger RNAPII binding on one haplotype promoted the formation of long-range regulatory loops with distal genes, thereby contributing to allele-biased transcription at a subset of loci, even when promoter-proximal RNAPII occupancy was comparable between alleles. These results demonstrate that subtle differences in RNAPII engagement and 3D regulatory wiring between parental haplotypes can reshape transcriptional output in hybrids, providing new insights into the mechanisms underlying the allelic regulation of gene expression.

Allele-specific chromatin interactions↗
PubMed1978

H-2.28, an alloantigenic marker allelic to H-2.1, is expressed on all three known types of H-2 molecules.

Each allele at the K or D region of the H-2 complex produces two kinds of "allelic" or mutually exclusive antigenic characteristics: its unique private specificity and a public specificity(ies) of either the H-2.28 or H-2.1 family. The private specificities of the K and D regions are expressed on H-2K and H-2D molecules, respectively. The D region produces another molecule, H-2L, which lacks the H-2K and H-2D private specificity but exhibits the H-2.28 or H-2.1 specificity. We analyzed the expression of the H-2.28 determinants on H-2K, H-2D, and H-2L molecules. When an antiserum against H-2.28 is used to sensitize cells where it can react with only H-2K molecules or H-2D molecules, by subsequent elution antibodies against H-2.28 are recovered that can also react with H-2L molecules. Hence, determinants reactive with antibodies against H-2.28 are present on H-2L as well as on H-2K and H-2D molecules. The expression of the H-2.28/H-2.1 polymorphism on all three known types of H-2 molecules, without some obvious relation to the private specificities, suggests that the antigenic determinants of these two kinds of allelic systems (private in contrast to H-2.28/H-2.1) may be controlled by separate genes, even when they are expressed on the same molecule.

Animals↗
PubMed1979

Population genetics of Drosophila amylase. II. Geographic patterns in D. pseudoobscura.

Morph frequencies of three related polymorphisms were determined in ten natural populations of Drosophila pseudoobscura. They are the well-known inversion polymorphism of the third chromosome and the polymorphism for alpha-amylase produced by the structural gene Amy (which resides on the third chromosome). The third polymorphism was for tissue-specific expression of Amy in adult midguts; a total of 13 different patterns of activity have been observed. The preceding paper (Powell and Lichtenfels 1979) reports evidence that the variation in Amy expression is under polygenic control. Here we show that the polymorphism for midgut patterns occurs in natural populations and is not an artifact of laboratory rearing.--From population to population, Amy allele frequencies and frequencies of inversions belonging to different phylads vary coordinately. The geographic variation in alpha-amylase midgut activity patterns is uncorrelated with that for the other two types of polymorphisms. Furthermore, no correlation was detected between activity pattern(s) and Amy genotype(s) when both were assayed in the same individual.--These results imply that whatever the evolutionary-ecological forces are that control frequencies of the structural gene variants, they are not the same factors that control the frequencies of polymorphic genetic factors responsible for the tissue-specific expression of the enzyme.

Alleles↗
PubMed1978

Gene expression in euploid human hybrid cells: ouabain resistance is codominant.

Single-step mutations to ouabain resistance have been induced in Lesch-Nyhan diploid fibroblasts carrying a variant G6PD isozyme (OuaR/HGPRT-/G6PDA). Two of these mutant strains, differing in the degree of ouabain resistance, were fused with wild-type human diploid fibroblasts (OuaS/HGPRT+/G6PDB) and hybrids isolated in doubly selective medium, ouabain + HAT (HOT). Four hybrids, identified by G6PD heteropolymers and stable tetraploid karyotypes, expressed ouabain resistance intermediate to that of the parents. The degree of ouabain resistance was influenced by the specific mutant allele of the OuaR parent, indicating both mutant and wild-type alleles are simultaneously expressed in hybrid cells. Intraspecific hybrids of this kind are especially suited to studies of gene regulation because all relevant genes present and the number of alleles at each locus is known.

Alleles↗
PubMed1976

Synchronous allelic expression at the glucosephosphate isomerase A and B loci in interspecific sunfish hybrids.

Allelic isozymes of glucosephosphate isomerase at the Gpi-A and -B loci were separated by starch gel electrophoresis in the warmouth (Lepomis gulosus) and green sunfish (L. cyanellus). The specific tissue distributions and developmental expressions of the GPI-A2, -AB, and -B2 isozymes were not different between these two species. The synchrony of allelic expression in normal intraspecific sunfish crosses was demonstrated by means of an electrophoretic variant at the Gpi-B locus. In embryos formed from warmouth x green sunfish hybrid crosses, the paternal GPI-A2 isozymes were first expressed at the same time in both reciprocal hybrids, at 21-25 hr after fertilization. The maternal and paternal GPI-B subunits were synchronously expressed in reciprocal hybrids just for prior to hatching. The parental allelic isozymes at both loci shoed codominant expression in all tissues of the mature F1 hybrids. These results are consistent with the absence of allelic asynchrony and inhibition in interspecific hybrids formed from more evolutionarily related species.

Age Factors↗
PubMed1977

In vitro secondary mixed leukocyte reaction (MLR). II. Interaction MLR determinants expressed by F1 cells.

T cells from strain A primed in vitro to (C57BL/6 x A/JF1 [(B6 x A)F1] cells respond better to restimulation by (B6 x A)F1 than by B6 or a 1:1 mixture of A and B6 cells. The increase in the response to F1 cells is specific and due to MLR determinants present on (B6 x A)F1 cells but not on either of the parental cell types. (B6 x A)F1 cells express more than one F1-specific MLR determinant, and this expression is dependent upon products of alleles of at least two loci within the major histocompatibility complex (MHC). Responsiveness to these F1-MLR determinants is apparently controlled by more than one locus within the MHC.

Animals↗
PubMed2026

Polysomal Profiling Coupled to Allele-Specific Proteomics Reveals an EIF4H TranSNP Allele Possessing Higher mRNA Translation Potential.

To search for genetic sources of allele-specific mRNA translation, we leveraged heterozygous polymorphisms and variants present in the exome of HCT116 colorectal adenocarcinoma-derived cells, computing allelic fractions from both total and polysome-associated RNA from RNA-Seq data. Allelic imbalance in polysomal RNA led us to nominate 52 coding variants associated with allele-specific mRNA translation, of which 16 are nonsynonymous. To validate instances of allele-specific translation, a proteomics workflow was developed that combines label-free shotgun analysis, high-pH reversed-phase peptide fractionation, and targeted parallel reaction monitoring using isotope-labeled peptide standards. Using this approach, we provide proof-of-concept validation of the heterozygous G>A, R183H missense single-nucleotide variant rs1554710467 in the eukaryotic initiation factor 4H (EIF4H) gene. The variant is present in two EIF4H alternatively spliced variants, which showed equivalent translation efficiency in HCT116 cells but differ in abundance. The alternative peptide containing H183 was significantly more abundant than the corresponding reference peptide containing R183, consistent with the over-representation of the alternative allele in polysomal RNA in HCT116 cells. A dual-fluorescence ribosome-stalling assay confirmed the enhanced translation potential of the variant allele. The two EIF4H allelic proteins exhibited similar stability and subpolysomal localization. This study demonstrates the feasibility of using allele-specific proteomics at the endogenous protein levels by exploiting heterozygous coding variants. Overall, our approach extends the toolbox available to investigate allele-specific differences in mRNA translation potential, a relatively underexplored layer of gene expression regulation that could reveal interindividual differences in disease-relevant phenotypes.

Humans↗
PubMed1978

On a regulatory gene controlling the expression of the murine lambda1 light chain.

We describe here two alleles, an allele of the lambda1 locus present in the SJL strain (rlambda1lo) and an allele of the lambda1 locus present in the BALB/c strain (rlambda1 +), of a regulatory gene locus which specifically influences the expression of the mouse lambda1 light chain structural gene. The rlambda1 regulatory gene is not linked to either the major histocompatibility complex or to the heavy-chain allogroup but appears to be linked to the lambda1 structural gene locus. In the homozygous state, the present of the rlambda1lo allele results in a 50-fold reduction in the number of lambda1 antigen-sensitive, bone-marrow derived lymphocytes (ASCs) compared to the presence of the rlambda1 + allele. However, those few lambda1ASCs present in rlambda1lo homozygotes can be induced normally to produce lambda1 light chains indistinguishable from those found in rlambda1 + homozygotes. The reduction in lambda1ASC's due to the rlambda1lo allele results both in a reduction in the amount of lambda1 Ig in the serum and also in a large variation in the magnitude of the lambda1 antibody response to alpha(1,3) dextran by individual animals. This variation permits the estimate that, on the average, 50 B cells of anti-alpha(1,3) specificity must be present per animal to permit a measurable response. Surprisingly, the expression of a gene locus regulating lambda1 light chain expression (rlambda1 locus) shows a clear gene dosage effect with rlambda1lo/rlambda1 + heterozygotes having 1/2 the number of lambda1ASCs and 1/2 the amount of serum lambda1 Ig as rlambda1 +/rlambda1 + homozygotes. This fact permits an analysis of the relationship between germ-line v-genes and their individual expression in serum Ig. The rlambda1 locus controls specifically a DNA-level event which occurs in stem cells as they become committed to lambda1 light chain expression. We postulate that the rlambda1 locus represents one of the DNA level recognition sites involved in the translocation event which places the vlambda1 and clambda1 structural genes in a transcriptional unit.

Animals↗
PubMed2025

Structure of a polymorphic repeat at the CACNA1C schizophrenia locus.

Genetic variation within intron 3 of the CACNA1C calcium channel gene is associated with schizophrenia and other neuropsychiatric disorders, but analysis of the causal variants and their effect is complicated by a nearby variable-number tandem repeat (VNTR). Here, we explored the structure and population variability of the CACNA1C intron 3 VNTR using 155 long-read genome assemblies from 78 diverse individuals. Based on sequence differences among repeat units, we clustered individual sequences into 7 VNTR structural alleles called Types. Three Types were related through large duplications, but the other Types diverged much earlier such that only 12 repeat units at the 5' end of the VNTR were shared across most Types. The most diverged Types were rare and present only in individuals with African ancestry, but a multiallelic structural polymorphism was present across populations at different frequencies, consistent with expansion of the VNTR preceding the emergence of early hominins. We demonstrated that this polymorphism was in complete linkage disequilibrium with fine-mapped schizophrenia variants from genome-wide association studies (GWAS), and that this risk haplotype was associated with decreased CACNA1C gene expression in the brain. Our work suggests that sequence variation within a human-specific VNTR affects gene expression, and provides a detailed characterization of new alleles at a flagship neuropsychiatric locus.

Variable-number tandem repeat↗