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Ying, K.

Publications and source records attributed to Ying, K..

25 records · Page 2Linked to original sources

Causal Epigenetic Age Uncouples Damage and Adaptation

Machine learning models based on DNA methylation data can predict biological age but often lack causal insights. By harnessing large-scale genetic data through epigenome-wide Mendelian Randomization, we identified CpG sites potentially causal for aging-related traits. Neither the existing epigenetic clocks nor age-related differential DNA methylation are enriched in these sites. These CpGs include sites that contribute to aging and protect against it, yet their combined contribution negatively affects age-related traits. We established a novel framework to introduce causal information into epigenetic clocks, resulting in DamAge and AdaptAge--clocks that track detrimental and adaptive methylation changes, respectively. DamAge correlates with adverse outcomes, including mortality, while AdaptAge is associated with beneficial adaptations. These causality-enriched clocks exhibit sensitivity to short-term interventions. Our findings provide a detailed land-scape of CpG sites with putative causal links to lifespan and healthspan, facilitating the development of aging biomarkers, assessing interventions, and studying reversibility of age-associated changes.

genetics↗

Nature of epigenetic aging from a single-cell perspective

Age-related changes in DNA methylation (DNAm) form the basis for the development of most robust predictors of age, epigenetic clocks, but a clear mechanistic basis for exactly what part of the aging process they quantify is lacking. Here, to clarify the nature of epigenetic aging, we juxtapose the aging dynamics of tissue and single-cell DNAm (scDNAm) with scDNAm changes during early development, and corroborate our analyses with a single-cell RNAseq analysis within the same multi-omics dataset. We show that epigenetic aging involves co-regulated changes, but it is dominated by the stochastic component, and this agrees with transcriptional coordination patterns. We further support the finding of stochastic epigenetic aging by direct tissue and single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated and stochastic CpG clusters showing consistent transcriptomic coordination patterns, providing new opportunities for targeting aging and evaluating longevity interventions.

systems biology↗

Epigenetic profiling and incidence of disrupted development point to gastrulation as aging ground zero in Xenopus laevis

Recent studies suggest the existence of a natural rejuvenation event during early embryonic development of mice, followed by epigenetic aging. Here, by profiling embryonic DNA methylation in the African clawed frog, Xenopus laevis, we found that the epigenetic entropy basepoint maps to the gastrulation stage of embryogenesis and corresponds to a rapid increase in embryo transcript abundance. We further developed a frog aging clock, revealing that this species epigenetically ages. Application of this clock to developmental stages identified a decrease in epigenetic age during early embryogenesis, with the minimal age reached around gastrulation. By examining individual developmental trajectories of 6,457 embryos, we found that this stage is also accompanied by a higher incidence of disrupted development. Taken together, our data point to gastrulation as a critical stage for aging and natural rejuvenation, characterized by the lowest epigenetic age, increased mortality, nadir of DNA methylation entropy and rapid increase in embryo transcript abundance, defining aging ground zero as the basepoint where rejuvenation ends and the aging process begins.

genetics↗

Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh Syndrome

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological aging process. Rapamycin, a drug that increases lifespan and health during normative aging also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh Syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh Syndrome. Here we show that another drug that extends lifespan and delays normative aging in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of mTOR inhibition. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression. This study provides the first evidence that alteration of the gut microbiome may impact severe mitochondrial disease and provides further support for the model that biological aging and severe mitochondrial disorders share underlying common mechanisms.

biochemistry↗

Intergenerational hormesis is regulated by heritable 18S rRNA methylation

Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labelling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans. We find that methylation is transmitted to descendants in proteins, RNA, DNA and lipids. We further find that in response to parental starvation, fed naive progeny display reduced fertility, increased heat stress resistance, and extended longevity. This intergenerational hormesis is accompanied by a heritable increase in N6-dimethyl adenosine (m6,2A) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified the conserved DIMT-1 as the m6,2A methyltransferase in C. elegans and find that dimt-1 is required for the intergenerational hormesis phenotypes. This study provides the first labeling and tracking of heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating the heritable response to starvation.

genetics↗

High-fidelity fast volumetric brain MRI using a hybrid denoising generative adversarial network (HDnGAN)

PurposeReducing scan times is important for wider adoption of high-resolution volumetric MRI in research and clinical practice. Emerging fast imaging and deep learning techniques provide promising strategies to accelerate volumetric MRI without compromising image quality. In this study, we aim to leverage an advanced fast imaging technique, wave-controlled aliasing in parallel imaging (Wave-CAIPI), and a novel denoising generative adversarial network (GAN) to achieve accelerated high-fidelity, high-signal-to-noise-ratio (SNR) volumetric MRI. Methods3D T2-weighted fluid-attenuated inversion recovery (FLAIR) image data were acquired on 33 multiple sclerosis (MS) patients using a prototype Wave-CAIPI sequence (acceleration factor R=3x2, 2.75 minutes) and a standard T2-SPACE FLAIR sequence (R=2, 7.25 minutes). A hybrid denoising GAN entitled "HDnGAN" composed of a 3D generator (i.e., a modified 3D U-Net entitled MU-Net) and a 2D discriminator was proposed to denoise Wave-CAIPI images with the standard FLAIR images as the target. HDnGAN was trained and validated on data from 25 MS patients by minimizing a combined content loss (i.e., mean squared error (MSE)) and adversarial loss with adjustable weight{lambda} , and evaluated on data from 8 patients unseen during training. The quality of HDnGAN-denoised images was compared to those from other denoising methods including AONLM, BM4D, MU-Net, and 3D GAN in terms of their similarity to standard FLAIR images, quantified using MSE and VGG perceptual loss. The images from different methods were assessed by two neuroradiologists using a five-point score regarding sharpness, SNR, lesion conspicuity, and overall quality. Finally, the performance of these denoising methods was compared at higher noise levels using simulated data with added Rician noise. ResultsHDnGAN effectively denoised noisy Wave-CAIPI images with sharpness and rich textural details, which could be adjusted by controlling{lambda} . Quantitatively, HDnGAN ({lambda}=10-3) achieved low MSE (7.43 x10-4{+/-}0.94x10-4) and the lowest VGG perceptual loss (1.09x10-2{+/-}0.18x10-2). The reader study showed that HDnGAN ({lambda}=10-3) significantly improved the SNR of Wave-CAIPI images (4.19{+/-}0.39 vs. 2.94{+/-}0.24, P<0.001), outperformed AONLM (4.25{+/-}0.56 vs. 3.75{+/-}0.90, P=0.015), BM4D (3.31{+/-}0.46, P<0.001), MU-Net (3.13{+/-}0.99, P<0.001) and 3D GAN ({lambda}=10-3) (3.31{+/-}0.46, P<0.001) regarding image sharpness, and outperformed MU-Net (4.21{+/-}0.67 vs. 3.29{+/-}1.28, P<0.001) and 3D GAN ({lambda}=10-3) (3.5{+/-}0.82, P=0.001) regarding lesion conspicuity. The overall quality score of HDnGAN ({lambda}=10-3) (4.25{+/-}0.43) was significantly higher than those from Wave-CAIPI (3.69{+/-}0.46, P=0.003), BM4D (3.50{+/-}0.71, P=0.001), MU-Net (3.25{+/-}0.75, P<0.001), and 3D GAN ({lambda}=10-3) (3.50{+/-}0.50, P<0.001), with no significant difference compared to standard FLAIR images (4.38{+/-}0.48, P=0.333). The advantages of HDnGAN over other methods were more obvious at higher noise levels. ConclusionHDnGAN provides robust and feasible denoising while preserving rich textural detail in empirical volumetric MRI data and is superior on both quantitative and qualitative evaluation compared to the original Wave-CAIPI images and images denoised using standard methods. HDnGAN concurrently benefits from the improved image synthesis performance of the 3D convolution and the increased number of samples for training the 2D discriminator from a limited number of subjects. Our study supports the use of HDnGAN in combination with modern fast imaging techniques such as Wave-CAIPI to achieve high-fidelity fast volumetric MRI.

neuroscience↗

Transcriptome-wide map of m6A circRNAs identified in hypoxic pulmonary hypertension rat model

Hypoxic pulmonary hypertension (HPH) is a lethal disease. CircRNAs and m6A circRNAs have been reported to be associated with cancer progression, but the expression profiling of m6A circRNAs has not been identified in HPH. This study was to investigate the transcriptome-wide map of m6A circRNAs in HPH. In this study, hypoxia-induced PH rat model was established. Total RNA was extracted and purified from lungs of rats, then circRNAs were detected and annotated by RNA-seq analysis. m6A RNA Immunoprecipitation (MeRIP) was performed following rRNA depletion, and RNA-seq library was constructed. CircRNA-miRNA-mRNA co-expression network was also constructed. In vitro, total m6A was measured. m6A circXpo6 and m6A circTmtc3 were detected in pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs) exposed to 21% O2 and 1% O2 for 48 h, respectively. m6A abundance in 166 circRNAs was significantly upregulated and m6A abundance in 191 circRNAs was significantly downregulated in lungs of HPH rats. m6A abundance in circRNAs was significantly reduced in hypoxia in vitro. m6A circRNAs were mainly derived from single exons of protein-coding genes. m6A influenced the circRNA-miRNA-mRNA co-expression network in hypoxia. m6A circXpo6 and m6A circTmtc3 were downregulated in hypoxia. In general, our study firstly identified the transcriptome-wide map of m6A circRNAs in HPH. m6A level in circRNAs was decreased in lungs of HPH rats and in PASMCs and PAECs exposed to hypoxia. Downregulated or upregulated m6A level influenced circRNA-miRNA-mRNA co-expression network in HPH. Moreover, we firstly identified two downregulated m6A circRNAs in HPH: circXpo6 and circTmtc3. We suggested that m6A circRNAs may be used as a potential diagnostic marker or therapy target in the future.\n\nAuthor summaryHPH is a disease with great morbidity and mortality. It is often caused by chronic hypoxic lung diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases. It lacks effective therapy methods so far. CircRNAs are a type of non-coding RNAs and can be used as biomarkers because they are differentially enriched in specific cell types or tissues and not easily degraded. m6A is identified as the most universal modification on non-coding RNAs in eukaryotes. CircRNAs can be modified by m6A. m6A circRNAs in HPH is not well understood yet. Here we identify the transcriptome-wide map of m6A circRNAs in HPH. We elucidate that m6A level in circRNAs is decreased in lungs of HPH rats and in PASMCs and PAECs exposed to hypoxia. We find that downregulated or upregulated m6A level influences circRNA- miRNA-mRNA co-expression network in HPH. Moreover, we are the first to identify two downregulated m6A circRNAs in HPH: circXpo6 and circTmtc3. We suggest that m6A circRNAs may be used as a potential diagnostic marker or therapy target in the future.

genetics↗