Yilin Xie

All Publications

• The Long Non-coding RNA Landscape of Endurance Exercise Training. Molecular metabolism Bonilauri, B., Smith, G. R., Raja, A. N., Jimenez-Morales, D., Ahmed, A., Jin, C., Sparks, L. M., Walsh, M. J., Montgomery, S. B., Bodine, S. C., Ashley, E. A., Lindholm, M. E. 2026: 102358

  Abstract

  Long non-coding RNAs (lncRNAs) regulate multiple cellular processes. However, knowledge of the responses and regulatory functions of lncRNAs in physical exercise and training remains limited. As part of the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we conducted a comprehensive analysis of lncRNA expression patterns in 18 tissues after an 8-week progressive endurance training program in rats. The lncRNA expression pattern was largely tissue-specific. In total, 759 unique lncRNAs were found to be differentially expressed across all tissues, generally displaying lower abundance, shorter transcript length, and reduced GC content compared with protein-coding genes. The most pronounced changes were observed in white and brown adipose tissues, the hypothalamus, and the adrenal gland. In the two skeletal muscle tissues investigated, only two lncRNAs were commonly differentially expressed. White and brown adipose tissues revealed a correlation between upregulated differentially expressed lncRNAs and coding genes associated with immune regulation. We identified substantial sex differences in the lncRNA regulatory landscape in response to exercise training. This comprehensive tissue-specific characterization of exercise-responsive lncRNAs opens new avenues for understanding exercise as molecular medicine and may inform the development of lncRNA-targeted therapeutics that harness the beneficial effects of exercise.

  View details for DOI 10.1016/j.molmet.2026.102358

  View details for PubMedID 42019922

• Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart. bioRxiv : the preprint server for biology Marderstein, A. R., Kundu, S., Padhi, E. M., Deshpande, S., Wang, A., Robb, E., Sun, Y., Yun, C. M., Pomales-Matos, D., Xie, Y., Nachun, D., Jessa, S., Kundaje, A., Montgomery, S. B. 2025

  Abstract

  Whole genome sequencing has identified over a billion non-coding variants in humans, while GWAS has revealed the non-coding genome as a significant contributor to disease. However, prioritizing causal common and rare non-coding variants in human disease, and understanding how selective pressures have shaped the non-coding genome, remains a significant challenge. Here, we predicted the effects of 15 million variants with deep learning models trained on single-cell ATAC-seq across 132 cellular contexts in adult and fetal brain and heart, producing nearly two billion context-specific predictions. Using these predictions, we distinguish candidate causal variants underlying human traits and diseases and their context-specific effects. While common variant effects are more cell-type-specific, rare variants exert more cell-type-shared regulatory effects, with selective pressures particularly targeting variants affecting fetal brain neurons. To prioritize de novo mutations with extreme regulatory effects, we developed FLARE, a context-specific functional genomic model of constraint. FLARE outperformed other methods in prioritizing case mutations from autism-affected families near syndromic autism-associated genes; for example, identifying mutation outliers near CNTNAP2 that would be missed by alternative approaches. Overall, our findings demonstrate the potential of integrating single-cell maps with population genetics and deep learning-based variant effect prediction to elucidate mechanisms of development and disease-ultimately, supporting the notion that genetic contributions to neurodevelopmental disorders are predominantly rare.

  View details for DOI 10.1101/2025.02.18.638922

  View details for PubMedID 40027628

  View details for PubMedCentralID PMC11870466

• Single-cell multi-omics map of human fetal blood in Down syndrome. Nature Marderstein, A. R., De Zuani, M., Moeller, R., Bezney, J., Padhi, E. M., Wong, S., Coorens, T. H., Xie, Y., Xue, H., Montgomery, S. B., Cvejic, A. 2024

  Abstract

  Down syndrome predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood1-3. Here, to understand dysregulated haematopoiesis in Down syndrome, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human fetal liver and bone marrow samples from 3 fetuses with disomy and 15 fetuses with trisomy. We found that differences in gene expression in Down syndrome were dependent on both cell type and environment. Furthermore, we found multiple lines of evidence that haematopoietic stem cells (HSCs) in Down syndrome are 'primed' to differentiate. We subsequently established a Down syndrome-specific map linking non-coding elements to genes in disomic and trisomic HSCs using 10X multiome data. By integrating this map with genetic variants associated with blood cell counts, we discovered that trisomy restructured regulatory interactions to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Furthermore, as mutations in Down syndrome display a signature of oxidative stress4,5, we validated both increased mitochondrial mass and oxidative stress in Down syndrome, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Together, our single-cell, multi-omic resource provides a high-resolution molecular map of fetal haematopoiesis in Down syndrome and indicates significant regulatory restructuring giving rise to co-occurring haematological conditions.

  View details for DOI 10.1038/s41586-024-07946-4

  View details for PubMedID 39322663

  View details for PubMedCentralID 2480572

• Centromere repositioning and shifts in wheat evolution PLANT COMMUNICATIONS Zhao, J., Xie, Y., Kong, C., Lu, Z., Jia, H., Ma, Z., Zhang, Y., Cui, D., Ru, Z., Wang, Y., Appels, R., Jia, J., Zhang, X. 2023; 4 (4): 100556

  Abstract

  The centromere is the region of a chromosome that directs its separation and plays an important role in cell division and reproduction of organisms. Elucidating the dynamics of centromeres is an alternative strategy for exploring the evolution of wheat. Here, we comprehensively analyzed centromeres from the de novo-assembled common wheat cultivar Aikang58 (AK58), Chinese Spring (CS), and all sequenced diploid and tetraploid ancestors by chromatin immunoprecipitation sequencing, whole-genome bisulfite sequencing, RNA sequencing, assay for transposase-accessible chromatin using sequencing, and comparative genomics. We found that centromere-associated sequences were concentrated during tetraploidization and hexaploidization. Centromeric repeats of wheat (CRWs) have undergone expansion during wheat evolution, with strong interweaving between the A and B subgenomes post tetraploidization. We found that CENH3 prefers to bind with younger CRWs, as directly supported by immunocolocalization on two chromosomes (1A and 2A) of wild emmer wheat with dicentromeric regions, only one of which bound with CENH3. In a comparison of AK58 with CS, obvious centromere repositioning was detected on chromosomes 1B, 3D, and 4D. The active centromeres showed a unique combination of lower CG but higher CHH and CHG methylation levels. We also found that centromeric chromatin was more open than pericentromeric chromatin, with higher levels of gene expression but lower gene density. Frequent introgression between tetraploid and hexaploid wheat also had a strong influence on centromere position on the same chromosome. This study also showed that active wheat centromeres were genetically and epigenetically determined.

  View details for DOI 10.1016/j.xplc.2023.100556

  View details for Web of Science ID 001038258400001

  View details for PubMedID 36739481

  View details for PubMedCentralID PMC10398676

• Enhancer transcription detected in the nascent transcriptomic landscape of bread wheat GENOME BIOLOGY Xie, Y., Chen, Y., Li, Z., Zhu, J., Liu, M., Zhang, Y., Dong, Z. 2022; 23 (1): 109

  Abstract

  The precise spatiotemporal gene expression is orchestrated by enhancers that lack general sequence features and thus are difficult to be computationally identified. By nascent RNA sequencing combined with epigenome profiling, we detect active transcription of enhancers from the complex bread wheat genome. We find that genes associated with transcriptional enhancers are expressed at significantly higher levels, and enhancer RNA is more precise and robust in predicting enhancer activity compared to chromatin features. We demonstrate that sub-genome-biased enhancer transcription could drive sub-genome-biased gene expression. This study highlights enhancer transcription as a hallmark in regulating gene expression in wheat.

  View details for DOI 10.1186/s13059-022-02675-1

  View details for Web of Science ID 000789818500001

  View details for PubMedID 35501845

  View details for PubMedCentralID PMC9063354

• Homology-mediated inter-chromosomal interactions in hexaploid wheat lead to specific subgenome territories following polyploidization and introgression GENOME BIOLOGY Jia, J., Xie, Y., Cheng, J., Kong, C., Wang, M., Gao, L., Zhao, F., Guo, J., Wang, K., Li, G., Cui, D., Hu, T., Zhao, G., Wang, D., Ru, Z., Zhang, Y. 2021; 22 (1): 26

  Abstract

  Polyploidization and introgression are major events driving plant genome evolution and influencing crop breeding. However, the mechanisms underlying the higher-order chromatin organization of subgenomes and alien chromosomes are largely unknown.We probe the three-dimensional chromatin architecture of Aikang 58 (AK58), a widely cultivated allohexaploid wheat variety in China carrying the 1RS/1BL translocation chromosome. The regions involved in inter-chromosomal interactions, both within and between subgenomes, have highly similar sequences. Subgenome-specific territories tend to be connected by subgenome-dominant homologous transposable elements (TEs). The alien 1RS chromosomal arm, which was introgressed from rye and differs from its wheat counterpart, has relatively few inter-chromosome interactions with wheat chromosomes. An analysis of local chromatin structures reveals topologically associating domain (TAD)-like regions covering 52% of the AK58 genome, the boundaries of which are enriched with active genes, zinc-finger factor-binding motifs, CHH methylation, and 24-nt small RNAs. The chromatin loops are mostly localized around TAD boundaries, and the number of gene loops is positively associated with gene activity.The present study reveals the impact of the genetic sequence context on the higher-order chromatin structure and subgenome stability in hexaploid wheat. Specifically, we characterized the sequence homology-mediated inter-chromosome interactions and the non-canonical role of subgenome-biased TEs. Our findings may have profound implications for future investigations of the interplay between genetic sequences and higher-order structures and their consequences on polyploid genome evolution and introgression-based breeding of crop plants.

  View details for DOI 10.1186/s13059-020-02225-7

  View details for Web of Science ID 000609225600004

  View details for PubMedID 33419466

  View details for PubMedCentralID PMC7792079