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At least 19 recordsLinked to original sources
PubMed2026

Parent-of-origin specific allelic expression in outbreeding Arabidopsis arenosa identifies antagonistic parental enrichment in protein degradation pathways.

In plants, the epigenetic phenomenon of parent-of-origin allele-specific expression occurs mainly in the triploid endosperm. Although well studied in inbreeding Arabidopsis thaliana, genomic imprinting has been less investigated in outcrossers. In order to investigate a wider role of parental-specific allelic expression, we have analyzed imprinting in whole seeds of the obligate outbreeder Arabidopsis arenosa. High-throughput analysis of imprinting in outbreeding species is hampered by the lack of reference genomes and available sequenced accessions. High degree of allelic variation in outbreeding species may also limit the analysis to loci with less variation. We developed a reference-independent pipeline to detect parental-specific reads. Using different accessions in reciprocal crosses, we detected more than 70 paternally biased imprinted genes and > 500 maternally biased genes. Paternally biased genes showed major enrichment for proteins with ubiquitin protein transferase and ligase activity. Maternally biased genes were enriched for protein pathways directly counteracting paternally enriched genes. Here, we demonstrate an alignment-free protocol to identify imprinted genes that may be successfully applied for imprinting studies in other highly heterozygous outcrossing species. Our results suggest a unique role of genomic imprinting affecting post-transcriptional gene regulation in outbreeding A. arenosa.

Arabidopsis arenosa↗
PubMed2025

Bayesian estimation of allele-specific expression in the presence of phasing uncertainty.

MOTIVATION: Allele-specific expression (ASE) analyses aim to detect imbalanced expression of maternal versus paternal copies of an autosomal gene. Such allelic imbalance can result from a variety of cis-acting causes, including disruptive mutations within one copy of a gene that impact the stability of transcripts, as well as regulatory variants outside the gene that impact transcription initiation. Current methods for ASE estimation suffer from a number of shortcomings, such as relying on only one variant within a gene, assuming perfect phasing information across multiple variants within a gene, or failing to account for alignment biases and possible genotyping errors. RESULTS: We developed BEASTIE, a Bayesian hierarchical model designed for precise ASE quantification at the gene level, based on given genotypes and RNA-Seq data. BEASTIE addresses the complexities of allelic mapping bias, genotyping error, and phasing errors by incorporating empirical phasing error rates derived from Genome-in-a-Bottle individual NA12878. BEASTIE surpasses existing methods in accuracy, especially in scenarios with high phasing errors. This improvement is critical for identifying rare genetic variants often obscured by such errors. Through rigorous validation on simulated data and application to real data from the 1000 Genomes Project, we establish the robustness of BEASTIE. These findings underscore the value of BEASTIE in revealing patterns of ASE across gene sets and pathways. AVAILABILITY AND IMPLEMENTATION: The software is freely available from Github (https://github.com/x811zou/BEASTIE); and Zendo (DOI: 10.5281/zenodo.15062124).

Bayes Theorem↗
PubMed2026

Cis-regulatory variation in the MdCKX6 promoter is associated with allele-specific expression and fruit size in apple.

Fruit size is a key determinant of apple fruit quality and market value and is strongly influenced by phytohormone-regulated cell proliferation and expansion during early fruit development. Cytokinin oxidase/dehydrogenase (CKX) enzymes regulate cytokinin homeostasis by irreversibly degrading active cytokinins, but the contribution of natural variation in CKX genes to fruit size remains poorly understood. Here, we identified MdCKX6 as a candidate regulator of fruit growth in apple (Malus domestica). MdCKX6 exhibited pronounced allele-specific expression during fruit development in the cultivar 'Royal Gala'. Sequence analysis identified a promoter SNP associated with differential promoter activity and allele-specific expression. Genotyping of diverse apple cultivars and wild Malus accessions revealed a significant association between MdCKX6 promoter genotype and fruit size. Cultivars carrying low-expression alleles produced larger fruits, whereas high-expression alleles were associated with smaller fruits. To investigate gene function, MdCKX6 was overexpressed in tomato, resulting in reduced fruit size. Histological analyses of the transgenic tomato fruit revealed smaller pericarp cells. Transcriptome analysis of transgenic fruits revealed widespread changes in genes associated with cell-cycle regulation, cell wall modification, hormone-related processes, and transcriptional regulation. Together, these results identify MdCKX6 as a potential negative regulator of apple fruit growth and reveal an association between cis-regulatory variants, gene expression, and fruit size. This study provides new insights into the role of cytokinin metabolism in fruit development and highlights regulatory variation in MdCKX6 as a potential target for apple breeding.

Malus↗
PubMed2026

Network-based stratification of allele-specific expression reveals patient subgroups in Huntington's disease.

MOTIVATION: Huntington's disease (HD) exhibits substantial variability in age of onset and disease progression that is not fully explained by CAG repeat length alone. Part of this residual variation is heritable, implicating additional genetic mechanisms. cis-regulatory variation, genetic variants that alter transcription and splicing of nearby genes, represents one such mechanism that can be quantified through allele-specific expression (ASE) analysis. However, methods for integrating ASE profiles into patient stratification frameworks remain underdeveloped, particularly for rare diseases with small cohorts and sparse data. RESULTS: We adapt a network-based stratification algorithm, originally developed for somatic tumour mutations, to ASE data. By propagating gene-level ASE imbalance profiles through a protein-protein interaction network, we stratified 20 HD patients into three distinct biological patient subgroups. Differential gene expression analysis highlights neuroinflammatory pathways, including microglial activation, immune cell activation, and cytokine regulation, as key sources of inter-patient heterogeneity, while differential ASE analysis implicates proteasomal and ubiquitin-dependent protein catabolic processes, immune activation, and central nervous system development. Intersection of differentially imbalanced and expressed genes identified FAM181B as a candidate gene with potential eQTL-mediated regulation, supported by independent cis-eQTL evidence for rs3780 in the caudate and putamen, the primary HD-affected striatal regions. FAM181B encodes a nuclear protein expressed in neural tissues acting as an interactor of the Hippo pathway TEAD transcription factors, implicating transcriptional regulatory variation as a potential contributor to molecular heterogeneity between patient subgroups. Differences in cortical and striatal neuropathological scores between clusters, even when adjusted for CAG repeat length, provide clinical support for the biological relevance of the identified subgroups. AVAILABILITY: All analysis code, Docker containers, and conda environments are available at https://github.com/macsbio/HD-ASE-NBS.

Huntington Disease↗
PubMed2026

Exploring genomic regions regulating the liver transcriptome and energy homeostasis in pigs.

In pigs, energy homeostasis has an impact on meat quality and health. In a Duroc pig population, 30 quantitative trait locus (QTL) regions associated with fatty acid (FA) composition in adipose tissue, plasma, liver and muscle were previously identified. Mapping of expression quantitative trait locus (eQTL) regions will provide a molecular hypothesis for genotype-phenotype interactions and may allow the identification of shared causal variants, key to increasing our understanding of the genetic regulation of FA composition and energy homeostasis. However, gene expression is impacted by environmental factors, while individual-level allelic imbalance (AI) can be more reliable and can be surveyed via allelic-specific expression (ASE) analysis. Furthermore, treatment of ASE as a quantitative trait allows the identification of allele-specific expression quantitative trait loci (aseQTLs), which are variants whose heterozygosity is linked to the AI of a nearby single-nucleotide polymorphism (SNP), pointing to regulatory elements. In this study, liver was selected as a key metabolic hub with an important role in the regulation of energy homeostasis, and 310 liver RNA sequencing samples were analysed using a combination of (1) eQTL mapping, (2) ASE analysis, and (3) aseQTL mapping methods. A total of 2 188 eQTL regions were identified, mostly cis-eQTL regions (73.17%). ASE analysis reported 1 964 ASE SNPs, associated with 633 genes. Finally, aseQTL mapping reported 64 172 aseQTL, associated with the AI of 31 genes. Colocalisation analysis combined with ASE analysis showed that the expression of FADS1 and FADS2 genes is associated with the polyunsaturated FA composition in several tissues, where microRNA regulation may be present. Finally, in the DGAT2 gene, annotated in a QTL region associated with multiple FAs in adipose tissue, ASE revealed allelic imbalance in the 3' untranslated region (UTR) of this gene. Allelic differential expression can be caused by a 13-bp insertion affecting messenger RNA stability, previously described, exemplifying how allelic imbalance is caused by a post-transcriptional regulatory mechanism undetectable by eQTL mapping. Furthermore, aseQTLs were associated with this gene, linked to a previously identified copy number variant not yet associated with DGAT2 expression. These results demonstrate how ASE analysis and aseQTL mapping can complement eQTL mapping, as they resolved a complex region affected by allelic heterogeneity, a main confounding effect of QTL mapping. In conclusion, the combination of eQTL mapping, ASE analysis and aseQTL mapping allowed the characterisation of the regulation of liver gene expression, improving our understanding of the genetic determinism of energy homeostasis.

Allele-specific expression↗
PubMed2011

Identification of transcriptome SNPs between Xiphophorus lines and species for assessing allele specific gene expression within F₁ interspecies hybrids.

Variations in gene expression are essential for the evolution of novel phenotypes and for speciation. Studying allelic specific gene expression (ASGE) within interspecies hybrids provides a unique opportunity to reveal underlying mechanisms of genetic variation. Using Xiphophorus interspecies hybrid fishes and high-throughput next generation sequencing technology, we were able to assess variations between two closely related vertebrate species, Xiphophorus maculatus and Xiphophorus couchianus, and their F(1) interspecies hybrids. We constructed transcriptome-wide SNP polymorphism sets between two highly inbred X. maculatus lines (JP 163 A and B), and between X. maculatus and a second species, X. couchianus. The X. maculatus JP 163 A and B parental lines have been separated in the laboratory for ≈70 years and we were able to identify SNPs at a resolution of 1 SNP per 49 kb of transcriptome. In contrast, SNP polymorphisms between X. couchianus and X. maculatus species, which diverged ≈5-10 million years ago, were identified about every 700 bp. Using 6524 transcripts with identified SNPs between the two parental species (X. maculatus and X. couchianus), we mapped RNA-seq reads to determine ASGE within F(1) interspecies hybrids. We developed an in silico X. couchianus transcriptome by replacing 90,788 SNP bases for X. maculatus transcriptome with the consensus X. couchianus SNP bases and provide evidence that this procedure overcomes read mapping biases. Employment of the in silico reference transcriptome and tolerating 5 mismatches during read mapping allow direct assessment of ASGE in the F(1) interspecies hybrids. Overall, these results show that Xiphophorus is a tractable vertebrate experimental model to investigate how genetic variations that occur during speciation may affect gene interactions and the regulation of gene expression.

Alleles↗
PubMed2026

DirectASRM: uncovering allele-specific post-transcriptional RNA modifications through direct RNA sequencing.

SUMMARY: We developed DirectASRM, a comprehensive database for the systematic identification, integration, and annotation of allele-specific RNA modifications (ASRMs) from direct RNA sequencing data. DirectASRM enables single-base, transcript-level detection of ASRMs across multiple RNA modification types, diverse organisms and condition-specific contexts. The database further evaluates the confidence of each ASRM-SNP pair association within isoform context by jointly considering statistical evidence of allelic modification imbalance and independent support from external next-generation sequencing (NGS) - based RNA modification resources. DirectASRM also provides extensive functional annotations for ASRMs and their associated variants, including intra-sample transcript-level allele-specific expression (ASE) and allele-specific splicing, as well as additional post-transcriptional regulatory features such as miRNA binding, circRNA, RNA-protein interactions, and disease relevance. Overall, DirectASRM serves as a comprehensive resource that supports systematic investigation of the potential functional impact of genetic variants in epitranscriptomic regulation. AVAILABILITY AND IMPLEMENTATION: DirectASRM database is freely accessible at http://modinfor.com/DirectASRM/. DirectASRM pipeline is available at GitHub (https://github.com/jiayin1101/DirectASRM_pipeline) and Zenodo (DOI: https://doi.org/10.5281/zenodo.19876077).

Alleles↗
PubMed2026

Gene expression is stable despite widespread cis and trans regulatory divergence in Saccharomyces yeasts.

Regulatory evolution can alter phenotypes, but cis- and trans-regulatory mechanisms may also diverge extensively while total transcript abundance remains stable. Comparisons of parental expression with allele-specific expression in F1 hybrids provide a framework for separating cis- and trans-regulatory effects because both parental alleles are measured in a shared trans-regulatory environment. Here, we analyzed RNA sequencing data from Saccharomyces cerevisiae, Saccharomyces paradoxus, and their F1 hybrid. Among the 4,164 genes with sufficient allele-specific support for strict classification, 2,134 (51.2%) showed detectable cis and/or trans regulatory divergence. However, hybrid expression remained largely conserved, with 81.5% of genes not significantly different from either parent. Compensatory cis-trans divergence predominated over reinforcing divergence; cross-replicate estimation reduced the apparent magnitude of this excess, but opposite-sign effects remained predominant in all 20 non-overlapping replicate comparisons. To connect gene expression to genome sequence, we analyzed the strongly cis-diverged locus LYS2 and found species differences in promoter architecture, including an S. cerevisiae-specific AT-rich insertion, altered spacing among candidate regulatory features, and a promoter-proximal TATA-like element unique to S. cerevisiae. Sequence-based nucleosome prediction suggests that these differences create a broader promoter-proximal nucleosome-depleted region in S. cerevisiae than in S. paradoxus. We also quantified allele-resolved intron retention and found that allele-resolved intron retention was broadly conserved, with only rare locus-specific hybrid-associated shifts. Together, these results show that regulatory divergence is widespread but often buffered in the hybrid, whereas intron-retention divergence is comparatively limited.

Saccharomyces↗
PubMed2026

Gene expression is stable despite widespread cis and trans regulatory divergence in Saccharomyces yeasts.

Regulatory evolution can alter phenotypes, but cis- and trans-regulatory mechanisms may also diverge extensively while total transcript abundance remains stable. Comparisons of parental expression with allele-specific expression in F1 hybrids provide a framework for separating cis- and trans-regulatory effects because both parental alleles are measured in a shared trans-regulatory environment. Here, we analyzed RNA sequencing data from Saccharomyces cerevisiae, Saccharomyces paradoxus, and their F1 hybrid. Regulatory divergence was widespread, with 61.3% of tested orthologs showing significant divergence in at least one cis or trans component. However, hybrid expression remained largely conserved, with 81.6% of genes not significantly different from either parent. Compensatory cis-trans divergence predominated over reinforcing divergence, consistent with widespread buffering of transcript abundance. To connect genome-wide patterns to mechanism, we analyzed the strongly cis-diverged locus LYS2 and found species differences in promoter architecture, including an S. cerevisiae-specific AT-rich insertion, altered spacing among candidate regulatory features, and a promoter-proximal TATA-like element unique to S. cerevisiae. Sequence-based nucleosome prediction suggests that these differences create a broader promoter-proximal nucleosome-depleted region in S. cerevisiae than in S. paradoxus. We also quantified allele-resolved intron retention and found that splicing was broadly conserved, with only rare locus-specific hybrid-associated shifts. Together, these results show that regulatory divergence is widespread but often buffered in the hybrid, whereas post-transcriptional divergence is comparatively limited.

Gene expression↗
PubMed2025

Comparative Embryology and Transcriptomics of Asellus infernus, an Isopod Crustacean From Sulfidic Groundwater.

Sulfidic caves are harsh and extreme environments characterized by limited oxygen, low pH, and the presence of hydrogen sulfide. Amazingly, animals can live in sulfidic caves, one such animal being Asellus infernus, a representative of the Asellus aquaticus species complex, originating from Movile Cave and from old wells that represent windows of access to a sulfidic groundwater ecosystem located in southeast Romania. Little previous work has been done on lab-reared populations of A. infernus as they have been historically difficult to raise in the lab. Here, we develop resources for A. infernus, examining questions of timing of morphological differences in cave versus surface individuals, whether the environment (lab-bred vs. wild-caught) influenced size characteristics, and the genes and pathways showing differential expression between cave and surface samples. We found that A. infernus did not develop pigmentation embryonically, and juveniles had increased body length and longer antenna II as compared to surface individuals. Furthermore, we found that some of these measures differed between wild-caught and lab-reared juveniles for a given population, indicating that environmental differences can also influence these size characteristics. In addition, differential expression between cave and surface samples and allele-specific expression studies within F1 hybrids identified multiple genes, including those involved in sulfide metabolism and phototransduction. Strikingly, molecular convergence of genes involved in sulfide detoxification was observed between A. infernus and previous work on a fish that lives in both cave and sulfidic environments, Poecilia mexicana. In sum, we were able to develop embryonic and genomic tools for A. infernus, a model for understanding cave adaptation and adaptation to sulfidic environments.

Animals↗
PubMed2025

Dynamic allelic expression in mouse mammary glands across the adult developmental cycle.

The mammary gland, which primarily develops postnatally, undergoes significant changes during pregnancy and lactation to facilitate milk production. Through the generation and analysis of 480 transcriptomes, we provide the most detailed allelic expression map of the mammary gland, cataloguing cell-type-specific expression from ex-vivo purified cell populations over 10 developmental stages, enabling comparative analysis. The work identifies genes involved in the mammary gland cycle, parental-origin-specific and genetic background-specific expression at cellular and temporal resolution, genes associated with human lactation disorders and breast cancer. Genomic imprinting, a mechanism regulating gene expression based on parental origin, is crucial for controlling gene dosage and stem cell potential throughout development. The analysis identified 25 imprinted genes monoallelically expressed in the mammary gland, with several showing allele-specific expression in distinct cell types. No novel imprinted genes were identified and the absence of biallelically expressed imprinted genes suggests that, unlike in brain, selective absence of imprinting does not regulate gene dosage in the mammary gland. This research highlights transcriptional dynamics within mammary gland cells and identifies novel candidate genes potentially significant in the tissue during pregnancy and lactation. Overall, this comprehensive atlas represents a valuable resource for future studies on expression and transcriptional dynamics in mammary cells.

Animals↗
PubMed2026

Parent-of-origin effects on allelic expression bias in interspecific poplar hybrids.

In hybrid plants, phenotypic outcomes are governed by interactions between the two parental genomes. However, the mechanisms underlying the interplay of divergent regulatory networks from these genomes remain poorly understood. In this study, we compared gene-level and allele-specific expression patterns, as well as differentially enriched pathways between F₁ and complex backcross (CBC) lines derived from a natural interspecific hybrid population of Populus fremontii (Pf) and P. angustifolia (Pa). Metabolic differences between Pf and Pa which exhibit low and high levels respectively of phenylpropanoid-derived condensed tannins were leveraged. Using individualized transcriptome references, differential expression and clustering analyses revealed CBC-biased and F₁-biased expression for genes involved in phenylpropanoid metabolism and photosynthesis, respectively. Biased expression of these genes at the allele level was also observed in F1. At the whole-transcriptome level, Pa-biased genes predominated in F₁ hybrids, and Pa alleles displayed more conserved expression patterns than Pf alleles across examined samples. Further analyses indicated that allelic expression bias was significantly associated with parental origin, which could be driven by sequence variations in cis-regulatory elements and differences in CpG island length. Our findings demonstrate strong parent-of-origin effects on divergent regulatory networks governing gene expression in poplar hybrids and provide clues for strategic parental selection tailored to specific metabolic pathways of interest.

cis-regulation↗
PubMed2025

Quantifying HLA transcripts by genotype in chimeric mixtures at single-cell resolution.

Gene products from the highly variable major histocompatibility locus, including HLA, are essential for self-recognition and immune surveillance of malignancy. Following allogeneic hematopoietic cell transplantation (alloHCT), genetic and epigenetic alterations in HLA can drive disease recurrence, making precise HLA assessment critical for determining future therapy. However, current methods lack the sensitivity to quantify HLA transcripts at the single-cell level, limiting their clinical utility. We introduce scrHLA-typing, a novel technique that accurately identifies and quantifies HLA transcripts in single cells using long-read sequencing. When applied to samples from patients with post-transplant relapse, scrHLA-typing successfully detected HLA allele-specific expression, across a range of levels of donor-recipient chimerism, at clinically actionable levels. By characterizing allele expression in residual leukemia cells, our assay identified differences in expression patterns among patients. This capability highlights scrHLA-typing's potential to improve risk stratification and guide the selection of appropriate salvage therapies, enhancing personalized treatment strategies after relapse.

Journal Article↗
PubMed2026

Haplotype-specific expression of a terpene synthase underlies linalool variation in the grapevine cultivar Riesling.

Grapevine cultivars vary widely in monoterpenoid content, yet the genetic and regulatory mechanisms underlying this variation remain poorly characterized beyond highly aromatic Muscat types. We profiled free volatiles and monoterpenoid glycosides in a Riesling × Cabernet Sauvignon F1 mapping population, revealing extensive variation and transgressive segregation consistent with multigenic control. QTL mapping identified 70 significant loci associated with 48 volatile compounds and monoterpene glycosides, including two major QTLs explaining 33.6% and 33.4% of phenotypic variance in (3S)-linalool accumulation. Integration of haplotype-resolved transcriptomics with metabolite data, enabled by a chromosome-scale diploid Riesling genome assembly, resolved a (3S)-linalool/nerolidol synthase cluster on chromosome 10 and identified VviTPS54 as the strongest candidate underlying linalool variation. VviTPS54 exhibited haplotype-specific expression strongly correlated with (3S)-linalool accumulation across genotypes, while no QTL was detected at the 1-deoxy-D-xylulose-5-phosphate synthase 1 (VviDXS1) locus previously identified in Muscat cultivars. In addition, VviDXS1 expression was not correlated with terpene levels, indicating that regulatory variation within terpene synthase clusters, rather than methylerythritol phosphate (MEP) pathway flux, drives monoterpenoid composition in this population. These results establish regulatory variation of terpene synthases as a key mechanism underlying monoterpenoid diversity in grapevine and demonstrate that resolving such variation requires haplotype-phased genome assemblies coupled with haplotype-resolved transcriptomics to detect allele-specific expression differences at complex, heterozygous loci.

Grapevine↗
PubMed2025

Cis-regulatory evolution of Wnt-family genes contributes to a morphological difference between silkworm species.

Closely related species often exhibit distinct morphologies that can contribute to species-specific adaptations and reproductive isolation. One example are Lepidopteran caterpillar appendages, such as the "caudal horn" of Bombycoidea moths, which have evolved substantial morphological diversity among species in this group. Using interspecific crosses, we identify the genetic basis of the caudal horn size difference between Bombyx mori and its closest relative B. mandarina. The three largest of eight QTL account for one third the mean horn length difference between the species. The largest of these, on chromosome 4, encompasses a conserved Wnt-family gene cluster, key upstream regulators that are well-known for their roles in morphological diversification in animals. Using allele-specific expression analysis and CRISPR/Cas9 knockouts, we show that tissue-specific cis-regulatory changes to Wnt1 and Wnt6 contribute to the species difference in caudal horn size. This kind of modularity enables highly pleiotropic genes, including key upstream growth regulators, to contribute to the evolution of morphological traits without causing widespread deleterious effects.

Journal Article↗
PubMed2026

Integrative Long-Read Multi-Omics of a Patient With GPI Deficiency: A Molecular Case Study of a Candidate Dual-Effect GPI Variant.

The molecular determinants of phenotypic severity in red cell enzymopathies are often obscured by the disconnect between coding sequence variants and their regulatory landscapes. Here we present a single-patient molecular case study that uses an integrative multi-omic approach-combining short-read WGS, PacBio HiFi long-read sequencing, native CpG methylation profiling, and Iso-Seq full-length transcriptomics-to characterize a severe, transfusion-dependent hemolytic anaemia. We identified a compound heterozygous state in the glucose-6-phosphate isomerase (GPI) gene, with no wild-type allele present. One allele (Haplotype 1) carried a missense variant (p.His191Arg); the other (Haplotype 2) carried a distinct missense variant, c.1414C>T (p.Arg472Cys), previously reported as biochemically unstable. Long-read phasing placed the two variants in trans. Allele-resolved transcript counts showed a directionally consistent but statistically non-significant trend toward higher expression of Haplotype 2 across two Iso-Seq replicates. Notably, the c.1414C>T transition abolishes a local CpG dinucleotide; in a small number of haplotype-2 reads spanning this position, the corresponding cytosine on the wild-type/Haplotype-1 background was methylated. We did not measure GPI protein abundance, enzymatic activity, or stability in this patient, and we do not establish that methylation at this site regulates GPI transcription. On the basis of these correlative observations in a single patient, we propose-as a hypothesis for future testing-that a coding variant might simultaneously perturb protein stability and disrupt a local epigenetic mark, and we outline the experiments required to test whether such a dual effect contributes to disease. This case illustrates the value of integrative long-read multi-omics for generating mechanistic hypotheses about variants of uncertain significance, while underscoring that causal claims require dedicated functional validation.

Humans↗
PubMed2025

G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells.

Elevated glucagon concentrations have been reported in patients with type 2 diabetes (T2D). A critical role for α cell-intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the glucose-6-phosphatase catalytic subunit 2 (G6PC2) locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c. Here, we found that trait-associated variants in the G6PC2 promoter are located in open chromatin not just in β but also in α cells and documented allele-specific G6PC2 expression of linked variants in human α cells. Using α cell-specific gene ablation of G6pc2 in mice, we showed that this gene plays a critical role in controlling glucose suppression of amino acid-stimulated glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology, findings that we confirmed in primary human α cells. Collectively, our data demonstrate that G6PC2 affects glycemic control via its action in α cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.

Glucagon↗
PubMed2025

Intermediately Methylated Regions in Normal Cells Are Epimutation Hotspots in Cancer.

DNA methylation is altered in all cancers, but the mechanisms responsible for these changes are not well understood. Using data from 100 primary samples, we show that regions with intermediate methylation in normal hematopoietic cells are hotspots for stable, clonal epimutations in acute myeloid leukemia. Analysis of hematopoietic stem cell clones demonstrated that intermediate methylation at epimutation hotspots reflects random allele-specific methylation and expression at the single cell level, representing a previously unrecognized form of somatically acquired imprinting. We identified somatically imprinted regions in other tissues and show they are epimutation hotspots in other cancer types. This demonstrates that random allele-specific methylation is both a general property of normal cells, and a vulnerability that renders them susceptible to cooperating events and clonal selection during cancer.

Journal Article↗