Cell Genom. 2023 Dec 6;3(12):100455. doi: 10.1016/j.xgen.2023.100455. eCollection 2023 Dec 13.

ABSTRACT

Recent advances in long-read sequencing technologies have not only dramatically increased sequencing read length but also have improved the accuracy of detecting chemical modifications to the canonical nucleotide bases, thus opening exciting venues to investigate the epigenome. Currently, the ability to visualize modified bases from long-read sequencing data in genome browsers is still limited, preventing users from easily and fully exploring these type of data. To address this limitation, the WashU Epigenome Browser introduces the modbed track type, which provides visualization of modification details in each single read as well as aggregated modifications of individual or multiple molecules across a dynamic range of resolutions. The modbed file can be uploaded for visualization as a local track or viewed with an accessible URL freely on the WashU Epigenome Browser at https://epigenomegateway.wustl.edu/.

PMID:38116122 | PMC:PMC10726485 | DOI:10.1016/j.xgen.2023.100455

Cell Genom. 2023 Dec 13;3(12):100458. doi: 10.1016/j.xgen.2023.100458. eCollection 2023 Dec 13.

ABSTRACT

Short tandem repeats (STRs) are genomic regions consisting of repeated sequences of 1-6 bp in succession. Single-nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) do not fully capture STR effects. To study these effects, we imputed 445,720 STRs into genotype arrays from 408,153 White British UK Biobank participants and tested for association with 44 blood phenotypes. Using two fine-mapping methods, we identify 119 candidate causal STR-trait associations and estimate that STRs account for 5.2%-7.6% of causal variants identifiable from GWASs for these traits. These are among the strongest associations for multiple phenotypes, including a coding CTG repeat associated with apolipoprotein B levels, a promoter CGG repeat with platelet traits, and an intronic poly(A) repeat with mean platelet volume. Our study suggests that STRs make widespread contributions to complex traits, provides stringently selected candidate causal STRs, and demonstrates the need to consider a more complete view of genetic variation in GWASs.

PMID:38116119 | PMC:PMC10726533 | DOI:10.1016/j.xgen.2023.100458

BMC Genomics. 2023 Dec 19;24(1):790. doi: 10.1186/s12864-023-09875-4.

ABSTRACT

Transcriptome studies disentangle functional mechanisms of gene expression regulation and may elucidate the underlying biology of disease processes. However, the types of tissues currently collected typically assay a single post-mortem timepoint or are limited to investigating cell types found in blood. Noninvasive tissues may improve disease-relevant discovery by enabling more complex longitudinal study designs, by capturing different and potentially more applicable cell types, and by increasing sample sizes due to reduced collection costs and possible higher enrollment from vulnerable populations. Here, we develop methods for sampling noninvasive biospecimens, investigate their performance across commercial and in-house library preparations, characterize their biology, and assess the feasibility of using noninvasive tissues in a multitude of transcriptomic applications. We collected buccal swabs, hair follicles, saliva, and urine cell pellets from 19 individuals over three to four timepoints, for a total of 300 unique biological samples, which we then prepared with replicates across three library preparations, for a final tally of 472 transcriptomes. Of the four tissues we studied, we found hair follicles and urine cell pellets to be most promising due to the consistency of sample quality, the cell types and expression profiles we observed, and their performance in disease-relevant applications. This is the first study to thoroughly delineate biological and technical features of noninvasive samples and demonstrate their use in a wide array of transcriptomic and clinical analyses. We anticipate future use of these biospecimens will facilitate discovery and development of clinical applications.

PMID:38114913 | DOI:10.1186/s12864-023-09875-4

Commun Biol. 2023 Dec 19;6(1):1282. doi: 10.1038/s42003-023-05681-6.

ABSTRACT

Metagenomic-based studies have predicted an extraordinary number of potential antibiotic-resistance genes (ARGs). These ARGs are hidden in various environmental bacteria and may become a latent crisis for antibiotic therapy via horizontal gene transfer. In this study, we focus on a resistance gene cph, which encodes a phosphotransferase (Cph) that confers resistance to the antituberculosis drug capreomycin (CMN). Sequence Similarity Network (SSN) analysis classified 353 Cph homologues into five major clusters, where the proteins in cluster I were found in a broad range of actinobacteria. We examine the function and antibiotics targeted by three putative resistance proteins in cluster I via biochemical and protein structural analysis. Our findings reveal that these three proteins in cluster I confer resistance to CMN, highlighting an important aspect of CMN resistance within this gene family. This study contributes towards understanding the sequence-structure-function relationships of the phosphorylation resistance genes that confer resistance to CMN.

PMID:38114770 | DOI:10.1038/s42003-023-05681-6

Nat Med. 2023 Dec 19. doi: 10.1038/s41591-023-02676-y. Online ahead of print.

NO ABSTRACT

PMID:38114667 | DOI:10.1038/s41591-023-02676-y

Nat Commun. 2023 Dec 19;14(1):8435. doi: 10.1038/s41467-023-44195-x.

ABSTRACT

We previously reported the results of a randomized phase II trial (NCT02904954) in patients with early-stage non-small cell lung cancer (NSCLC) who were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined with immunomodulatory doses of stereotactic radiation (DRT). The trial met its primary endpoint of major pathological response, which was significantly higher following DRT with no new safety signals. Here, we report on the prespecified secondary endpoint of disease-free survival (DFS) regardless of treatment assignment and the prespecified exploratory analysis of DFS in each arm of the trial. DFS at 2 and 3 years across patients in both arms of the trial were 73% (95% CI: 62.1-84.5) and 65% (95% CI: 52.5-76.9) respectively. For the exploratory endpoint of DFS in each arm of the trial, three-year DFS was 63% (95% CI: 46.0-80.4) in the durvalumab monotherapy arm compared to 67% (95% CI: 49.6-83.4) in the dual therapy arm. In addition, we report post hoc exploratory analysis of progression-free survival as well as molecular correlates of response and recurrence through high-plex immunophenotyping of sequentially collected peripheral blood and gene expression profiles from resected tumors in both treatment arms. Together, our results contribute to the evolving landscape of neoadjuvant treatment regimens for NSCLC and identify easily measurable potential biomarkers of response and recurrence.

PMID:38114518 | DOI:10.1038/s41467-023-44195-x

Protein Sci. 2023 Dec 19:e4872. doi: 10.1002/pro.4872. Online ahead of print.

ABSTRACT

In order to survive extreme drying (anhydrobiosis), many organisms, spanning every kingdom of life, accumulate intrinsically disordered proteins (IDPs). For decades, the ability of anhydrobiosis-related IDPs to form transient amphipathic helices has been suggested to be important for promoting desiccation tolerance. However, evidence empirically supporting the necessity and/or sufficiency of helicity in mediating anhydrobiosis is lacking. Here we demonstrate that the linker region of CAHS D, a desiccation-related IDP from the tardigrade Hypsibius exemplaris, that contains significant helical structure, is the protective portion of this protein. Perturbing the sequence composition and grammar of the linker region of CAHS D, through the insertion of helix-breaking prolines, modulating the identity of charged residues, or replacement of hydrophobic amino acids with serine or glycine residues results in variants with different degrees of helical structure. Importantly, correlation of protective capacity and helical content in variants generated through different helix perturbing modalities do not show as strong a trend, suggesting that while helicity is important it is not the only property that makes a protein protective during desiccation. These results provide direct evidence for the decades old theory that helicity of desiccation-related IDPs is linked to their anhydrobiotic capacity. This article is protected by copyright. All rights reserved.

PMID:38114424 | DOI:10.1002/pro.4872

Mol Plant Microbe Interact. 2023 Dec 19. doi: 10.1094/MPMI-11-23-0184-FI. Online ahead of print.

ABSTRACT

Xanthomonads, including Xanthomonas and Xylella species, constitute a large and significant group of economically and ecologically important plant pathogens. Up-to-date knowledge of these pathogens and their hosts is essential for the development of suitable control measures. Traditional review articles or book chapters have inherent limitations, including static content and rapid obsolescence. To address these challenges, we have developed a web-based knowledge platform dedicated to xanthomonads, inspired by the concept of living systematic reviews. This platform offers a dynamic resource that encompasses bacterial virulence factors, plant resistance genes, and tools for diagnostics and genetic diversity studies. Our goal is to facilitate access for newcomers to the field, provide continuing education opportunities for students, assist plant protection services with diagnostics, provide valuable information to breeders on sources of resistance and breeding targets, and offer comprehensive expert knowledge to other stakeholders interested in plant-pathogenic xanthomonads. This resource is available for queries and updates at https://euroxanth.ipn.pt.

PMID:38114082 | DOI:10.1094/MPMI-11-23-0184-FI

Clin Immunol. 2023 Dec 17:109874. doi: 10.1016/j.clim.2023.109874. Online ahead of print.

ABSTRACT

Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Faslpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (Sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1homo.lprhet strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.

PMID:38113962 | DOI:10.1016/j.clim.2023.109874

Int J Sports Med. 2023 Dec 19. doi: 10.1055/a-2233-0454. Online ahead of print.

ABSTRACT

This study aimed to assess the seasonal evolution of field-based and laboratory-based performance indicators in cyclists. Thirteen Junior male road cyclists (age 17.4±0.5 years) were followed-up during a season, which was divided in three phases: early-season (involving mainly training sessions), mid-season (including the first competitions), and late-season (including the major competitions of the season). During each phase, field-based power output data were registered for the assessment of maximum mean power values, and laboratory-based endurance (ramp test and simulated 8-minute time trial), muscle strength/power (squat, lunge, hip thrust) and body composition indicators (dual energy X-ray absorptiometry) were also assessed. A progressive (p<0.01) increase in maximum mean power values (e.g., 3.8±0.3 and 4.5±0.4 watts/kg in early and late-season, respectively, for 60-minute efforts) and on 8-minute time trial performance (i.e., 5.3±0.3 and 5.6±0.4 watts/kg, respectively) was observed through the season. Yet, more 'traditional' endurance indicators (i.e., ventilatory threshold, respiratory compensation point, or maximum oxygen uptake) seemed to show a ceiling effect beyond the mid-season. In addition, neither peak power output, body composition, nor muscle strength indicators, followed a similar pattern to the aforementioned field-based indicators. In summary, in Junior cyclists field-based indicators seem more sensitive to monitor changes in performance capacity than more 'traditional' laboratory-based markers.

PMID:38113921 | DOI:10.1055/a-2233-0454

Structure. 2023 Dec 14:S0969-2126(23)00413-6. doi: 10.1016/j.str.2023.11.011. Online ahead of print.

ABSTRACT

Major histocompatibility complex (MHC) proteins present peptides on the cell surface for T cell surveillance. Reliable in silico prediction of which peptides would be presented and which T cell receptors would recognize them is an important problem in structural immunology. Here, we introduce an AlphaFold-based pipeline for predicting the three-dimensional structures of peptide-MHC complexes for class I and class II MHC molecules. Our method demonstrates high accuracy, outperforming existing tools in class I modeling accuracy and class II peptide register prediction. We validate its performance and utility with new experimental data on a recently described cancer neoantigen/wild-type peptide pair and explore applications toward improving peptide-MHC binding prediction.

PMID:38113889 | DOI:10.1016/j.str.2023.11.011

Dev Cell. 2023 Dec 18;58(24):2914-2929.e7. doi: 10.1016/j.devcel.2023.11.013.

ABSTRACT

Low-grade chronic inflammation is a hallmark of ageing, associated with impaired tissue function and disease development. However, how cell-intrinsic and -extrinsic factors collectively establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using mouse organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of inflammaging. At the single-cell level, we found that inflammaging is established differently along the crypt-villus axis, with aged intestinal stem cells (ISCs) strongly upregulating major histocompatibility complex class II (MHC-II) genes. Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility at inflammation-associated loci in vivo and ex vivo, indicating cell-intrinsic inflammatory memory. Mechanistically, we show that the expression of inflammatory genes is dependent on STAT1 signaling. Together, our data identify that intestinal inflammaging in mice is promoted by a cell-intrinsic mechanism, stably propagated by ISCs, and associated with a disbalance in immune homeostasis.

PMID:38113852 | DOI:10.1016/j.devcel.2023.11.013

Int Immunopharmacol. 2023 Dec 18;127:111376. doi: 10.1016/j.intimp.2023.111376. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: RNA splicing is an essential step in regulating the gene posttranscriptional expression. Serine/arginine-rich splicing factors (SRSFs) are splicing regulators with vital roles in various tumors. Nevertheless, the expression patterns and functions of SRSFs in hepatocellular carcinoma (HCC) are not fully understood.

METHODS: Flow cytometry and immunofluorescent staining were used to determine the CD8+T cell infiltration. Orthotopic HCC model, lung metastasis model, DEN/CCl4 model, Srsf10△hep model, and Srsf10HepOE model were established to evaluate the role of SRSF10 in HCC and the efficacy of combination treatment.

RESULTS: SRSF10 was one of the most survival-relevant genes among SRSF members and was an independent prognostic factor for HCC. SRSF10 facilitated HCC growth and metastasis by suppressing CD8+T cell infiltration. Mechanistically, SRSF10 down-regulated the p53 protein by preventing the exon 6 skipping (exon 7 in mouse) mediated degradation of MDM4 transcript, thus inhibiting CD8+T cell infiltration. Elimination of CD8+T cells or overexpression of MDM4 removed the inhibitory role of SRSF10 knockdown in HCC growth and metastasis. SRSF10 also inhibited the IFNα/γ signaling pathway and promoted the HIF1α-mediated up-regulation of PD-L1 in HCC. Hepatocyte-specific SRSF10 deficiency alleviated the DEN/CCl4-induced HCC progression and metastasis, whereas hepatocyte-specific SRSF10 overexpression deteriorated these effects. Finally, SRSF10 knockdown enhanced the anti-PD-L1-mediated anti-tumor activity.

CONCLUSIONS: SRSF10 promoted HCC growth and metastasis by repressing CD8+T cell infiltration mediated by the MDM4-p53 axis. Furthermore, SRSF10 suppressed the IFNα/γ signaling pathway and induced the HIF1α signal mediated PD-L1 up-regulation. Targeting SRSF10 combined with anti-PD-L1 therapy showed promising efficacy.

PMID:38113691 | DOI:10.1016/j.intimp.2023.111376

J Chem Inf Model. 2023 Dec 19. doi: 10.1021/acs.jcim.3c01211. Online ahead of print.

ABSTRACT

Deep learning methods that predict protein-ligand binding have recently been used for structure-based virtual screening. Many such models have been trained using protein-ligand complexes with known crystal structures and activities from the PDBBind data set. However, because PDBbind only includes 20K complexes, models typically fail to generalize to new targets, and model performance is on par with models trained with only ligand information. Conversely, the ChEMBL database contains a wealth of chemical activity information but includes no information about binding poses. We introduce BigBind, a data set that maps ChEMBL activity data to proteins from the CrossDocked data set. BigBind comprises 583 K ligand activities and includes 3D structures of the protein binding pockets. Additionally, we augmented the data by adding an equal number of putative inactives for each target. Using this data, we developed Banana (basic neural network for binding affinity), a neural network-based model to classify active from inactive compounds, defined by a 10 μM cutoff. Our model achieved an AUC of 0.72 on BigBind's test set, while a ligand-only model achieved an AUC of 0.59. Furthermore, Banana achieved competitive performance on the LIT-PCBA benchmark (median EF1% 1.81) while running 16,000 times faster than molecular docking with Gnina. We suggest that Banana, as well as other models trained on this data set, will significantly improve the outcomes of prospective virtual screening tasks.

PMID:38113513 | DOI:10.1021/acs.jcim.3c01211

J Appl Lab Med. 2023 Dec 19:jfad111. doi: 10.1093/jalm/jfad111. Online ahead of print.

ABSTRACT

BACKGROUND: Developing and implementing new patient-centric strategies for drug trials lowers the barrier to participation for some patients by reducing the need to travel to research sites. In early chronic kidney disease (CKD) trials, albuminuria is the key measure for determining treatment effect prior to pivotal kidney outcome trials.

METHODS: To facilitate albuminuria sample collection outside of a clinical research site, we developed 2 quantitative microsampling methods to determine the urinary albumin to creatinine ratio (UACR). Readout was performed by LC-MS/MS.

RESULTS: For the Mitra device the within-batch precision (CV%) was 2.8% to 4.6% and the between-batch precision was 5.3% to 6.1%. Corresponding data for the Capitainer device were 4.0% to 8.6% and 6.7% to 9.0%, respectively. The storage stability at room temperature for 3 weeks was 98% to 103% for both devices. The recovery for the Mitra and Capitainer devices was 104% (SD 7.0%) and 95 (SD 7.4%), respectively. The inter-assay comparison of UACR assessment generated results that were indistinguishable regardless of microsampling technique. The accuracy based on LC-MS/MS vs analysis of neat urine using a clinical chemistry analyzer was assessed in a clinical setting, resulting in 102 ± 8.0% for the Mitra device and 95 ± 10.0% for the Capitainer device.

CONCLUSIONS: Both UACR microsampling measurements exhibit excellent accuracy and precision compared to a clinical chemistry analyzer using neat urine. We applied our patient-centric sampling strategy to subjects with heart failure in a clinical setting. Precise UACR measurements using quantitative microsampling at home would be beneficial in clinical drug development for kidney therapies.

PMID:38113397 | DOI:10.1093/jalm/jfad111

Sci Signal. 2023 Dec 19;16(816):eadg5289. doi: 10.1126/scisignal.adg5289. Epub 2023 Dec 19.

ABSTRACT

Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr42-to-Cys (Y42C) and Leu57-to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOAY42C exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOAL57V promotes DGC growth. In mouse gastric organoids with deletion of Cdh1, which encodes the cell adhesion protein E-cadherin, the expression of RHOAL57V, but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOAL57V also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOAL57V retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr42 and Leu57 in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOAL57V additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOAY42C. Our results reveal that RHOAL57V and RHOAY42C drive the development of DGC through distinct biochemical and signaling mechanisms.

PMID:38113333 | DOI:10.1126/scisignal.adg5289

Cell Rep. 2023 Dec 18;43(1):113593. doi: 10.1016/j.celrep.2023.113593. Online ahead of print.

ABSTRACT

Nuclear mRNA export via nuclear pore complexes is an essential step in eukaryotic gene expression. Although factors involved in mRNA transport have been characterized, a comprehensive mechanistic understanding of this process and its regulation is lacking. Here, we use single-RNA imaging in yeast to show that cells use mRNA retention to control mRNA export during stress. We demonstrate that, upon glucose withdrawal, the essential RNA-binding factor Nab2 forms RNA-dependent condensate-like structures in the nucleus. This coincides with a reduced abundance of the DEAD-box ATPase Dbp5 at the nuclear pore. Depleting Dbp5, and consequently blocking mRNA export, is necessary and sufficient to trigger Nab2 condensation. The state of Nab2 condensation influences the extent of nuclear mRNA accumulation and can be recapitulated in vitro, where Nab2 forms RNA-dependent liquid droplets. We hypothesize that cells use condensation to regulate mRNA export and control gene expression during stress.

PMID:38113140 | DOI:10.1016/j.celrep.2023.113593

Brief Bioinform. 2023 Nov 22;25(1):bbad458. doi: 10.1093/bib/bbad458.

ABSTRACT

Single-cell chromatin accessibility sequencing (scCAS) technologies have enabled characterizing the epigenomic heterogeneity of individual cells. However, the identification of features of scCAS data that are relevant to underlying biological processes remains a significant gap. Here, we introduce a novel method Cofea, to fill this gap. Through comprehensive experiments on 5 simulated and 54 real datasets, Cofea demonstrates its superiority in capturing cellular heterogeneity and facilitating downstream analysis. Applying this method to identification of cell type-specific peaks and candidate enhancers, as well as pathway enrichment analysis and partitioned heritability analysis, we illustrate the potential of Cofea to uncover functional biological process.

PMID:38113078 | DOI:10.1093/bib/bbad458

Cancer Treat Res. 2023;190:3-24. doi: 10.1007/978-3-031-45654-1_1.

ABSTRACT

RNA modifications have recently been recognized as essential posttranscriptional regulators of gene expression in eukaryotes. Investigations over the past decade have revealed that RNA chemical modifications have profound effects on tumor initiation, progression, refractory, and recurrence. Tumor cells are notorious for their robust plasticity in response to the stressful microenvironment and undergo metabolic adaptations to sustain rapid cell proliferation, which is termed as metabolic reprogramming. Meanwhile, cancer-associated metabolic reprogramming leads to substantial alterations of intracellular and extracellular metabolites, which further reshapes the tumor microenvironment (TME). Moreover, cancer cells compete with tumor-infiltrating immune cells for the limited nutrients to maintain their proliferation and function in the TME. In this chapter, we review recent interesting findings on the engagement of epitranscriptomic pathways, especially the ones associated with N6-methyladenosine (m6A), in the regulation of cancer metabolism and the surrounding microenvironment. We also discuss the promising therapeutic approaches targeting RNA modifications for anti-tumor therapy.

PMID:38112997 | DOI:10.1007/978-3-031-45654-1_1

Front Endocrinol (Lausanne). 2023 Dec 4;14:1266527. doi: 10.3389/fendo.2023.1266527. eCollection 2023.

ABSTRACT

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2) which drive the expression of different isoforms. P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2-HNF4α is indeed expressed in the normal adult liver at Zeitgeber time (ZT)9 and ZT21. Using exon swap mice that express only P2-HNF4α we show that this isoform orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions, including with different clock proteins at different times of the day leading to subtle differences in circadian gene regulation. Furthermore, deletion of the Clock gene alters the circadian oscillation of P2- (but not P1-)HNF4α RNA, revealing a complex feedback loop between the HNF4α isoforms and the hepatic clock. Finally, we demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α drives ketogenesis and is required for elevated levels of ketone bodies in female mice. Taken together, we propose that the highly conserved two-promoter structure of the Hnf4a gene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion.

PMID:38111711 | PMC:PMC10726135 | DOI:10.3389/fendo.2023.1266527