Yizhou Zhu

All Publications

• Ultrafine mapping of chromosome conformation at hundred basepair resolution reveals regulatory genome architecture. Proceedings of the National Academy of Sciences of the United States of America Zhu, Y., Rosenfeld, M. G., Suh, Y. 2023; 120 (45): e2313285120

  Abstract

  The resolution limit of chromatin conformation capture methodologies (3Cs) has restrained their application in detection of fine-level chromatin structure mediated by cis-regulatory elements (CREs). Here, we report two 3C-derived methods, Tri-4C and Tri-HiC, which utilize multirestriction enzyme digestions for ultrafine mapping of targeted and genome-wide chromatin interaction, respectively, at up to one hundred basepair resolution. Tri-4C identified CRE loop interaction networks and quantitatively revealed their alterations underlying dynamic gene control. Tri-HiC uncovered global fine-gauge regulatory interaction networks, identifying >20-fold more enhancer:promoter (E:P) loops than in situ Hi-C. In addition to vastly improved identification of subkilobase-sized E:P loops, Tri-HiC also uncovered interaction stripes and contact domain insulation from promoters and enhancers, revealing their loop extrusion behaviors resembling the topologically associating domain boundaries. Tri-4C and Tri-HiC provide robust approaches to achieve the high-resolution interactome maps required for characterizing fine-gauge regulatory chromatin interactions in analysis of development, homeostasis, and disease.

  View details for DOI 10.1073/pnas.2313285120

  View details for PubMedID 37922325

• Targeted sequencing of the 9p21.3 region reveals association with reduced disease risks in Ashkenazi Jewish centenarians AGING CELL Zhu, Y., Ryu, S., Tare, A., Barzilai, N., Atzmon, G., Suh, Y. 2023: e13962

  Abstract

  Genome-wide association studies (GWAS) have pinpointed the chromosomal locus 9p21.3 as a genetic hotspot for various age-related disorders. Common genetic variants in this locus are linked to multiple traits, including coronary artery diseases, cancers, and diabetes. Centenarians are known for their reduced risk and delayed onset of these conditions. To investigate whether this evasion of disease risks involves diminished genetic risks in the 9p21.3 locus, we sequenced this region in an Ashkenazi Jewish centenarian cohort (centenarians: n = 450, healthy controls: n = 500). Risk alleles associated with cancers, glaucoma, CAD, and T2D showed a significant depletion in centenarians. Furthermore, the risk and non-risk genotypes are linked to two distinct low-frequency variant profiles, enriched in controls and centenarians, respectively. Our findings provide evidence that the extreme longevity cohort is associated with collectively lower risks of multiple age-related diseases in the 9p21.3 locus.

  View details for DOI 10.1111/acel.13962

  View details for Web of Science ID 001051429600001

  View details for PubMedID 37605876

• Identification and functional validation of an enhancer variant in the 9p21.3 locus associated with glaucoma risk and elevated expression of p16INK4a. Aging cell Zhu, Y., Tazearslan, C., Rosenfeld, M. G., Fiser, A., Suh, Y. 2023

  Abstract

  Glaucoma is a leading cause of irreversible blindness, with advanced age being the single most significant risk factor. However, the mechanisms underlying the relationship between aging and glaucoma remain unclear. Genome-wide association studies (GWAS) have successfully identified genetic variants strongly associated with increased glaucoma risk. Understanding how these variants function in pathogenesis is crucial for translating genetic associations into molecular mechanisms and, ultimately, clinical applications. The chromosome 9p21.3 locus is among the most replicated glaucoma risk loci discovered by GWAS. Nonetheless, the absence of protein-coding genes in the locus makes interpreting the disease association challenging, leaving the causal variant and molecular mechanism elusive. In this study, we report the identification of a functional glaucoma risk variant, rs6475604. By employing computational and experimental methods, we demonstrated that rs6475604 resides in a repressive regulatory element. Risk allele of rs6475604 disrupts the binding of YY1, a transcription factor known to repress the expression of a neighboring gene in 9p21.3, p16INK4A, which plays a crucial role in cellular senescence and aging. These findings suggest that the glaucoma disease variant contributes to accelerated senescence, providing a molecular link between glaucoma risk and an essential cellular mechanism for human aging.

  View details for DOI 10.1111/acel.13908

  View details for PubMedID 37345431

• Identification and functional validation of an enhancer variant in the 9p21.3 locus associated with glaucoma risk and elevated expression of p16 INK4a. bioRxiv : the preprint server for biology Zhu, Y., Tazearslan, C., Rosenfeld, M. G., Fiser, A., Suh, Y. 2023

  Abstract

  Glaucoma is a leading cause of irreversible blindness, with advanced age being the single most significant risk factor. However, the mechanisms underlying the relationship between aging and glaucoma remain unclear. Genome-wide association studies (GWAS) have successfully identified genetic variants strongly associated with increased glaucoma risk. Understanding how these variants function in pathogenesis is crucial for translating genetic associations into molecular mechanisms and, ultimately, clinical applications. The chromosome 9p21.3 locus is among the most replicated glaucoma risk loci discovered by GWAS. Nonetheless, the absence of protein-coding genes in the locus makes interpreting the disease association challenging, leaving the causal variant and molecular mechanism elusive. In this study, we report the identification of a functional glaucoma risk variant, rs6475604. By employing computational and experimental methods, we demonstrated that rs6475604 resides in a repressive regulatory element. Risk allele of rs6475604 disrupts the binding of YY1, a transcription factor known to repress the expression of a neighboring gene in 9p21.3, p16INK4A, which plays a crucial role in cellular senescence and aging. These findings suggest that the glaucoma disease variant contributes to accelerated senescence, providing a molecular link between glaucoma risk and an essential cellular mechanism for human aging.

  View details for DOI 10.1101/2023.05.18.541339

  View details for PubMedID 37292862

• A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A (vol 41, e110393, 2022) EMBO JOURNAL Simon, M., Yang, J., Gigas, J., Earley, E. J., Hillpot, E., Zhang, L., Zagorulya, M., Tombline, G., Gilbert, M., Yuen, S. L., Pope, A., Van Meter, M., Emmrich, S., Firsanov, D., Athreya, A., Biashad, S., Han, J., Ryu, S., Tare, A., Zhu, Y., Hudgins, A., Atzmon, G., Barzilai, N., Wolfe, A., Moody, K., Garcia, B. A., Robbins, P. D., Vijg, J., Seluanov, A., Suh, Y., Gorbunova, V. 2023; 42 (3): e113326

  View details for DOI 10.15252/embj.2022113326

  View details for Web of Science ID 000924251100009

  View details for PubMedID 36722290

  View details for PubMedCentralID PMC9890223