PubMed HealthSearch

Biomedical subjects

Yu Sun

Publications and source records attributed to Yu Sun.

9 recordsLinked to original sources

The Jumonji C domain-containing proteins GmJMJ19 and GmJMJ20 link florigen signaling with epigenetic regulation of photoperiodic flowering and post-flowering plant height in soybean.

Soybean (Glycine max) is a photoperiod-sensitive legume whose latitudinal adaptation depends on the precise control of flowering time and plant height. Histone demethylases of the JmjC domain-containing (JMJ) protein family have been implicated in these processes across plant species, but their specific roles in soybean remain largely unexplored. Here, we identify soybean GmJMJ19 and GmJMJ20, two closely related JMJD5/KDM8 orthologs, as master epigenetic regulators that coordinately control both photoperiodic flowering and post-flowering plant height. Both genes exhibit intrinsic, rhythmic expression peaking at ZT12, and their encoded proteins physically interact with the florigen proteins FT2a and FT5a. Loss-of-function mutants display delayed flowering under long days (LDs) and increased plant height under both LDs and short days (SDs), whereas overexpression phenocopies the mutant flowering phenotype, indicating revealing a critical dosage requirement for proper function. Mechanistically, GmJMJ19 and GmJMJ20 are recruited by the FT/FD transcriptional complex to directly activate AP1a and AP1c expression through chromatin modulation. Population genomic analyses reveal distinct selection signatures: GmJMJ19 underwent sustained directional selection during cultivation, whereas GmJMJ20 experienced an early domestication sweep with limited subsequent change. Haplotype analysis identifies coordinated latitudinal clines, with the JMJ19H1/JMJ20H1 combination predominating at high latitudes to promote early flowering and limit height, while JMJ19H2/JMJ20H2 and wild JMJ19H3/JMJ20H3 alleles prevail at low latitudes, conferring later flowering and increased height. Collectively, our findings establish GmJMJ19 and GmJMJ20 as central chromatin regulators linking florigen signaling to downstream target expression and provide valuable allelic resources for breeding regionally adapted soybean varieties across a wide range of latitudinal environments.

Histone modulation

Integrative ATAC-seq and RNA-seq analysis reveals lactation performance between Sewa sheep and East Friesian sheep.

Lactation performance is a pivotal economic trait in sheep production, yet its underlying epigenetic regulatory mechanisms remain poorly understood. In the present study, we integrated ATAC-seq and RNA-seq to compare chromatin accessibility landscapes and transcriptomic in mammary gland tissues from Sewa sheep (SWS) and East Friesian sheep (EFS). Histological characterization revealed that SWS exhibited significantly smaller mammary acini area, smaller lipid droplet area, and reduced lipid droplet diameter compared to EFS. ATAC-seq analysis identified 15,902 differentially accessible regions (DARs) between the two breeds, with motif enrichment analysis uncovering key transcription factors potentially governing lactation traits. RNA-seq analysis revealed 1,163 differentially expressed genes (DEGs), which were involved in lactation regulation. Integrated analysis identified 441 overlapping genes, and enriched in glycolysis/gluconeogenesis (e.g., PGAM1, ENO1) and pyruvate metabolism (e.g., ACACA, ACSS1, ACYP1). Collectively, our study provides new insights into the epigenetic regulatory mechanisms underlying lactation performance differences in sheep.

Animals

Genome-wide CRISPR screen reveals PEX11B as a host restriction factor against ORFV through membrane fluidity regulation.

Host-pathogen interactions are shaped by cellular restriction factors that direct antiviral defenses. We built the first ovine genome-wide CRISPR knockout library in sheep testis (OA3.Ts) cells, targeting all protein-coding genes. Using this platform, we identified PEX11B, a peroxisomal membrane regulatory protein, as a strong restriction factor against orf virus (ORFV) infection. Removing PEX11B increased viral susceptibility and triggered severe cytopathic effects with membrane fusion and syncytia formation. Mechanistic studies showed that PEX11B knockout harmed peroxisomal integrity and disrupted lipid metabolism. This led to greater plasma membrane fluidity, creating a proviral environment that allowed more viral entry and replication. These results reveal a new antiviral function for PEX11B in blocking viral infection and underscore the importance of peroxisomal regulation in host-virus interactions.

Animals

Discovery of specific rhizosphere bacteria Rhodanobacter involved in KAI2-mediated drought tolerance in Arabidopsis.

The KARRIKIN INSENSITIVE 2 (KAI2) receptor has been reported to contribute to drought tolerance in Arabidopsis. However, the extent to which KAI2's function in drought tolerance depends on soil microbiota remains unclear. This study demonstrates that the rhizosphere microbiome is indispensable for KAI2-mediated drought tolerance. We isolated specific Rhodanobacter sp. and confirmed its role in enhancing drought tolerance in Arabidopsis. Notably, Rhodanobacter sp. was found to specifically secrete the key isoflavone daidzin. We found that daidzin had a similar function with KAI2 agonist, desmethyl-type germinone, and induced interaction between KAI2 and SUPRESSOR OF MORE AXILLARY GROWTH 2 1. Moreover, the exogenous application of daidzin enhanced drought tolerance by modulating the expression of karrikin response and drought-related genes, in a KAI2-dependent manner. Our findings suggest that the rhizosphere microbiome plays a crucial role in facilitating KAI2-mediated drought tolerance in Arabidopsis, with Rhodanobacter sp. contributing through the secretion of daidzin.

Arabidopsis

Systematic meta-analysis of the toxicities and side effects of the targeted drug lenvatinib.

BACKGROUND: Lenvatinib, an effective targeted drug for various cancers, has clinical medication safety concerns due to its toxicities and side effects. OBJECTIVE: This study evaluated lenvatinib-induced any adverse events (any AEs) and nine aspects: vascular toxicities related to the circulatory system (vascular toxicities, blood system, and heart), toxicities of the skin and its appendages (skin/subcutaneous tissue and taste system), toxicities of the respiratory system (respiratory, thoracic, and mediastinal and respiratory tract), toxicities of the nervous system (nervous system and general), toxicities of the digestive system (gastrointestinal and liver), toxicities of the urinary system, toxicities of the endocrine and metabolic system (endocrine and metabolism/nutrition), toxicities of the musculoskeletal system, and other severe toxicities. Toxicities and side effects were stratified by severity into any and &#x2265;3 grades for analysis. PATIENTS/MATERIALS AND METHODS: Multiple databases were searched for lenvatinib cancer clinical studies (cohort studies and randomized controlled trials) from inception to December 31, 2024; toxicity and side effect data were extracted and analyzed. RESULTS: Nine high-quality studies were included, showing that lenvatinib is effective in cancers but has notable toxicities. Taking hypertension as an example, for any grade, the risk ratio (RR) was 2.34 with a 95% confidence interval (CI) of [2.09, 2.62], a Z-value of 14.74, and a P-value <0.00001; for grade &#x2265;3, the RR was 2.60 with a 95% CI of [2.21, 3.06], a Z-value of 11.44, and a P-value <0.00001. CONCLUSION: Lenvatinib is effective for cancer but toxic, and this study supports its rational clinical use.

Humans

Macrolide-resistant Mycoplasma pneumoniae resurgence in Chinese children in 2023: a longitudinal, cross-sectional, genomic epidemiology study.

BACKGROUND: After a prolonged period of low detection rates, Mycoplasma pneumoniae resurged in China, during September to November, 2023, raising global concern. This study aims to gain a better understanding of the genetic mechanisms underlying the 2023 increase in cases and the evolutionary dynamics of the epidemic populations, which has been previously hampered due to limited genomic data of this pathogen. METHODS: We sequenced 685 M pneumoniae isolates, including 248 isolates from 11 Chinese provinces and municipalities in 2023 and 437 isolates from Beijing (2013-22). By analysing these isolates and 436 publicly global sequences, we reconstructed the pathogen's evolutionary history using time-calibrated phylogenies and effective population size inference. We investigated potential genomic variations contributing to the 2023 resurgence through genome-wide association study and conducted phylogeographic analysis of the 2023 isolates across China. FINDINGS: Two macrolide-resistant epidemic clusters (T1-2-EC1 and T2-2-EC2) were responsible for the 2023 resurgence in China. Both clusters, having acquired the 23S ribosomal RNA A2063G mutation conferring macrolide resistance, emerged in approximately 1997 and 2014, respectively, and subsequently outcompeted their predecessor populations. This coincided with China's large-scale adoption of azithromycin for paediatric community-acquired pneumonia around the early 2000s. Aside from macrolide resistance, T1-2-EC1 independently acquired 17 clade-specific mutations and T2-2-EC2 four clade-specific mutations, which could further explain their increased competitiveness. Whole-genome analysis revealed no resurgence-specific mutations in the 2023 isolates. Phylogeographic analysis showed rapid mixing of T1-2-EC1 isolates between different sampled regions within China. INTERPRETATION: Our study provides evidence that the 2023 resurgence in China is a continuation of the pre-COVID epidemic, rather than emergence of novel variants. The high prevalence of macrolide resistance and rapid intranational spread emphasise the urgent need for enhanced global surveillance of this pathogen. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China for Key Programs of China Grants, and Beijing High-Level Public Health Technical Talent Project.

Humans

KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.

UNLABELLED: NUP98 fusion oncoproteins (FO) are a hallmark of childhood acute myeloid leukemia. NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. In this study, we show that MYST family histone acetyltransferase (HAT) complex proteins, including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1, associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of KAT6A and KAT7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with menin inhibitor treatment, and was efficacious in menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r acute myeloid leukemia. SIGNIFICANCE: KAT6A and KAT7 associate with NUP98 FOs to drive leukemogenesis. Inhibition of their HAT activity is an effective therapeutic strategy in NUP98-r leukemias, including those resistant to menin inhibition. Moreover, combined KAT6A/7 and menin inhibition is synergistic, supporting clinical translation to improve outcomes for NUP98 FO-driven leukemias.

Humans

AAV gene therapy for autosomal recessive deafness 9: a single-arm trial.

Gene therapy for congenital deafness has shown promising results in children but lacks data in older populations. We conducted a single-arm trial of adeno-associated virus (AAV)-OTOF gene therapy using the Anc80L65 capsid in ten participants with autosomal recessive deafness&#x2009;9 aged 1.5 to 23.9&#x2009;years at five sites in China. The primary endpoints were safety and tolerability within 5&#x2009;years, and secondary endpoints assessed auditory function. Initial findings from the ten patients with 6-12 months of follow-up, including one patient who received two injections, revealed that the therapy was well tolerated, with 162 grade&#x2009;I/II adverse events. Decreased neutrophil percentage was the most common event (16 of 162). All ten participants had at least 6&#x2009;months of follow-up and improved their pure-tone-average hearing level from baseline 106&#x2009;&#xb1;&#x2009;9 (mean&#x2009;&#xb1;&#x2009;s.d.) to 52&#x2009;&#xb1;&#x2009;30 decibels (dB). Other secondary endpoints showed similar improvements, including the average click auditory brainstem response (ABR) threshold, the tone-burst ABR threshold and the auditory steady-state response (101&#x2009;&#xb1;&#x2009;1 to 48&#x2009;&#xb1;&#x2009;26&#x2009;dB, 91&#x2009;&#xb1;&#x2009;4 to 57&#x2009;&#xb1;&#x2009;19&#x2009;dB and 80&#x2009;&#xb1;&#x2009;14 to 64&#x2009;&#xb1;&#x2009;21&#x2009;dB, respectively). Post hoc analyses were conducted to evaluate the timecourse and factors contributing to the hearing improvement. Therapeutic effect was rapid, taking 1&#x2009;month to achieve most of the overall hearing improvement. On an individual level, click and tone-burst ABR thresholds, but not the auditory steady-state response, reliably predicted the behavioral pure-tone-average thresholds after 4&#x2009;months (R2&#x2009;=&#x2009;0.68, 0.73 and 0.17, respectively). An age-dependent therapeutic effect was observed, with optimal outcomes in 5- to 8-year-olds. These preliminary results show that AAV-OTOF was safe and well tolerated in patients ranging from toddlerhood to adulthood. The trial remains ongoing and requires extended follow-up to confirm the long-term safety and efficacy. ClinicalTrials.gov registration: NCT05901480 .

Humans

Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine-activated human aortic endothelial cells - Novel qualification markers for chronic disease risk factors and conditional DAMPs.

To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245).

Acetylation