Biology subjects

Zhan, K.

Publications and source records attributed to Zhan, K..

4 recordsLinked to original sources

bioRxiv2026

A multi-tissue epigenomic atlas links the sheep non-coding genome to domestication and complex traits

Non-coding regulatory variation drives complex traits, domestication, and evolutionary adaptation, yet the sheep genome lacks high-resolution functional annotation. Here we present SheepEpimap, a multi-tissue regulatory atlas harmonizing 516 CUT&Tag histone modifications, ATAC-seq, and RNA-seq datasets across 43 adult tissues in sheep. We annotated 2.93 million cis-regulatory elements, yielding 557,441 enhancer-gene pairs and 145,407 variants with allele-specific effects. By training a sequence-to-function deep-learning model, we decoded the base-pair syntax of chromatin accessibility, annotated transcription factor motif instances genome-wide, and constructed 12,210 tissue-specific gene regulatory networks (GRNs). Integrating this resource with multi-tissue expression quantitative trait loci, selection sweeps, and genome-wide association studies prioritized non-coding variants driving domestication and complex traits. Finally, cross-species analysis revealed that sequence-conserved, tissue-matched enhancers were significantly enriched in the heritability of complex traits and diseases in humans. In summary, SheepEpimap (https://genome.ucsc.edu/s/mengzhu/SheepEpimap) provides an open-access foundational ecosystem for sheep functional genomics, precision breeding, and comparative biology.

genetics↗

bioRxiv2025

Imlifidase and EndoS enables semi-allogeneic bone marrow engraftment in sensitized mice under reduced intensity conditioning

Patients in need of a hematopoietic stem cell transplant frequently have pre-existing donor-specific antibodies (DSA) which can impair engraftment. These patients often require intensified conditioning regimens, even in the setting of partially matched (semi-allogeneic) donors. Reducing the toxicity of conditioning and desensitization protocols is therefore a major goal. We previously showed that enzymatic desensitization of donor-specific IgG using imlifidase and EndoS improved murine bone marrow engraftment in donor sensitized, autoimmune-prone recipient mice. Conditioning included a 6 Gy total body irradiation, cyclophosphamide, bortezomib, and T cell depletion. In non-autoimmune prone semi-allogeneic recipients sensitized to the donor, we demonstrate that desensitisation with imlifidase and EndoS permits long-term donor bone marrow engraftment and induces tolerance to subsequent allogeneic skin grafts under a 3 Gy irradiation protocol. Enzymatic inactivation of DSA facilitates donor hematopoietic stem cell engraftment in allo-sensitized semi-allogeneic recipients in a reduced intensity conditioning protocol.

immunology↗

bioRxiv2022

Development of an affinity-enhanced clinical candidate TCR targeting NY-ESO-1 with optimal potency and high specificity

The clinical success of T-cell receptor (TCR)-based immunotherapy depends on the efficacy and specificity of TCRs. Naturally occurring TCRs have limited anti-tumor potency due to their low affinity for tumor antigens. Affinity enhancement is a promising strategy to generate highly potent TCRs. However, it is concerned that affinity-enhanced TCRs are prone to lose specificity. We isolated low affinity TCRs specific for NY-ESO-1157-165/HLA-A*02:01 from peripheral blood mononuclear cells of healthy donors. An affinity-enhanced TCR candidate with optimal affinity and specificity was generated using phage display and an extensive set of in vitro and in vivo assays. Alanine scanning mutagenesis showed that the TCR candidate retained specificity by making extensive contacts to the side chains of NY-ESO-1157-165 peptide. Adoptive transfer of T cells engineered with this candidate (termed TAEST16001) significantly inhibited tumor growth in subcutaneous, metastatic, and patient-derived xenograft (PDX) mouse tumor models. This study demonstrates that sophisticated engineering and screening techniques can be utilized to generate a clinical candidate TCR with potent anti-tumor activity without losing specificity. TAEST16001 was approved by the Center for Drug Evaluation (CDE) as the first TCR-based immunotherapy clinical trial in China (ClinicalTrials.gov Identifier: NCT03159585).

immunology↗

bioRxiv2019

ALI-1, candidate gene of B1 locus, is associated with awn length and grain weight in common wheat

Awn plays a vital role in the photosynthesis, grain production and drought tolerance of common wheat; however, works on the systematic identification or cloning of genes controlling wheat awn length (AL) were seldom reported. Here, we conducted the Genome-wide association study (GWAS) in 364 wheat accessions and identified 25 loci involved in the AL, including dominant awn suppressors B1, B2 and four homologs of awn controlling genes in rice and barley. Furthermore, the B1 locus was mapped to a 125-kb physical interval harboring two genes on chromosome 5AL through map-based cloning. As the candidate gene for B1 locus, a C2H2 zinc finger gene Awn Length Inhibitor 1 (ALI-1) expressed predominantly in the developing spike of awnless individuals and suppresses downstream genes transcriptionally. ALI-1 reduces cytokinin content and simultaneously restrains cytokinin signal transduction, which leads to a stagnation of cell proliferation and reduction of cell number in awn. Noteworthily, ali-1 was the first awn controlling locus that observed increasing grain length in wheat, which is a valuable supplemental attribution of awn on grain weight besides photosynthesis. Thus, ALI-1 pleiotropically regulates awn and grain development, and this work provides a strategy to achieve improved grain yield and address future extreme climate.\n\nHighlightALI-1, candidate gene of awn suppressing B1 locus, associates with awn length and grain length, providing a reacquaint of the effect of wheat awn on grain production.

plant biology↗