Biology subjects

zhang, h.

Publications and source records attributed to zhang, h..

10 recordsLinked to original sources

bioRxiv2026

A cis-regulatory variant in ASIP causes gray coat color in the donkey

BackgroundGray is one of the relatively rare coat colors in donkeys. The Hetian Gray donkey is a distinctive indigenous breed from the Xinjiang Uygur Autonomous Region of Northwestern China, characterized by progressive hair depigmentation with aging while retaining dark skin pigmentation. However, the genetic basis underlying this unique gray coat color phenotype remains unclear. ResultsTo elucidate the genetic basis, we conducted whole-genome resequencing of Gray and non-Gray donkeys. Genome-wide selection signature analyses identified a candidate region on chromosome 15. Subsequent fine-mapping using mass spectrometry-based genotyping of 42 loci refined the candidate interval and revealed a SNP within intron 2 of the ASIP gene, located in a genomic fragment with highly similar sequences, showing complete association with the gray coat color. Association analysis in an expanded population further confirmed a strong correlation between this variant and the gray phenotype. Gene expression analyses also supported the role of ASIP in regulating pigmentation in donkeys. ConclusionsThese findings identify a genetic determinant of gray coat color in donkeys and provide new insights into the molecular mechanisms underlying age-related depigmentation in domestic animals.

genomics↗

bioRxiv2025

Structural basis for ACT1 oligomerization induced by IL-17 receptor hetero-tetramer

The IL-17 receptors (IL-17Rs) play critical roles in immunity and inflammatory diseases. IL-17-induced heteromeric complexes between IL-17RA and another IL-17R trigger signaling by binding the downstream transducer ACT1 through interactions between their intracellular SEF/IL-17R (SEFIR) domains. The molecular mechanism of this process remains unclear. Here we present the cryo-EM structure of the complex of IL-17RA, IL-17RB and ACT1, showing that the IL-17RA and IL-17RB SEFIR domains form an asymmetric hetero-tetramer. The two IL-17RA SEFIR domains serve as the base to recruit ACT1, while IL-17RB stabilizes the IL-17RA dimer but makes no interaction with ACT1. IL-17RB, IL-17RA and multiple ACT1 together form a double-stranded helical assembly. The C-terminal SEFIR extension (SEFEX) of IL-17RA acts as a molecular tendril to help anchor the ACT1 protomers. The structural model is supported by our mutational analyses. These findings reveal the basis for the formation for the signalosome of the IL-17 receptors and ACT1 critical for immune signaling.

immunology↗

bioRxiv2025

Architecture and mechanism of a dual-enzyme retron system in prokaryotic immunity

Retrons are bacterial genetic retroelements encoding a reverse transcriptase (RT) and a non-coding RNA (ncRNA)-multi-copy single-stranded DNA (msDNA) hybrid. Diverse effector proteins or domains are found to associate with retrons, typically forming tripartite toxin-antitoxin systems involved in anti-phage defense. Although retrons have attracted growing interest in genome editing technologies, the mechanisms underlying most retron-mediated immune systems remain poorly understood. Here, we characterized a distinct quaternary retron system, Ec78, harboring a dual-enzymatic effector complex, in which the PtuA ATPase and PtuB nuclease act in concert to mediate phage clearance. The cryo-EM structure of the Ec78 complex adopts a flower-basket-like architecture, with two Ec78 retrons engaging the PtuAB effector complexes through a unique msDNA-insertion assembly mechanism. Interestingly, a sensing loop on the RT protein tightly monitors the length of the msDNA, which is likely responsible for phage detection and the subsequent release of the toxic effector complex. We further determined the cryo-EM structure of the retron-unbound effector complex, revealing an arginine-lysine finger loop on the PtuB nuclease that undergoes an ordered-to-disordered transition for enzymatic activation. Together, our work not only delineates the molecular basis underlying the Ec78 system in antiviral defense but also highlights the mechanistic diversity of retron systems in prokaryotic immunity.

biochemistry↗

bioRxiv2025

ShenQi Compound improves diabetes by modulating pancreatic mitochondrial energy metabolism in GK rats

PurposeShenQi Compound (SQC) is a traditional herbal formula that has long been utilized in the treatment of type 2 diabetes and its complications. The purpose of this study was to investigate the effect of SQC on mitochondrial energy metabolism in pancreatic tissues of spontaneously type 2 diabetic Goto-Kakizaki (GK) rats. MethodsGK rats were induced into a diabetic model using a high-fat diet. They were randomly divided into 3 groups (n=8): diabetes model group, SQC group (14.4 g/kg/d) and metformin (Met) group (0.1 g/kg/d). Another 8 Wistar rats were taken as controls. Weight, Blood glucose was monitored weekly in each group,After 12 weeks of gavage. Fasting blood glucose and lipid levels were evaluated, and histopathological changes in the pancreas were assessed by hematoxylin-eosin (HE) staining, serum fasting insulin(FINS) and pancreatic mitochondrial respiratory chain complex I-V (complexI-V) levels were measured by enzyme-linked immunosorbent assay (ELISA), reactive oxygen species ((ROS)) levels were detected by chemiluminescence, superoxide dismutase (SOD) levels were detected by xanthine oxidase, and glutathione (GSH) and adenosine triphosphate (ATP) levels were detected by colorimetric assay. And the uncoupling protein(UCP-2) protein and mRNA expression levels were detected by protein blotting and real-time quantitative PCR. ResultsSQC treatment significantly decreased (P<0.01) the levels of FBS, FINS,triglyceride s(TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) (P<0.01) and significantly increased (P<0.01) the levels of denser lipoprotein cholesterol (HDL-C) in GK rats. Pancreatic histopathological damage was improved after SQC treatment, and complexI to complexIV significantly decreased (P<0.05) and complexV, SOD and GSH significantly increased (P<0.05) in pancreatic tissues. In addition, SQC reduced the content of ROS and ATP in pancreatic tissues (P<0.01) and down-regulated UCP-2 protein and mRNA expression (P<0.01). ConclusionSQC improves glucose-lipid metabolism and attenuates pathological damage of pancreatic tissues in T2DM rats, possibly by regulating mitochondrial energy metabolism in pancreatic tissues. The effects of SQC are not well understood. These findings provide new insights into the mechanism of action of SQC in the treatment of T2DM and its associated neurodegenerative effects.

zoology↗

bioRxiv2025

Protenix - Advancing Structure Prediction Through a Comprehensive AlphaFold3 Reproduction

In this technical report, we present Protenix, a comprehensive reproduction of AlphaFold3 (AF3), aimed at advancing the field of biomolecular structure prediction. Protenix tackles the challenges of predicting complex interactions involving proteins, ligands, and nucleic acids, while enhancing accessibility and reproducibility. Across diverse benchmarks, including PoseBusters V2, low-homology PDB sets, and CASP15 RNA, Protenix achieves state-of-the-art performance in protein-ligand, protein-protein, and protein-nucleic acid predictions. We also address limitations, such as potential memorization effects, and outline future directions for improvement. By open-sourcing Protenix, we aim to democratize advanced structure prediction tools and accelerate interdisciplinary research in computational biology and drug discovery.

bioinformatics↗

bioRxiv2023

Structural basis for the concerted antiphage activity in the SIR2-HerA system

Recently, a novel two-gene bacterial defense system against phages, encoding a SIR2 NADase and a HerA translocase, has been identified. However, the molecular mechanism of the bacterial SIR2-HerA immune system remains unclear. Here, we determine the cryo-EM structures of SIR2, HerA and their complex in different functional states. The SIR2 proteins oligomerize into a dodecameric ring-shaped structure consisting of two layers of interlocked hexamers, in which each SIR2 unit exhibits an auto-inhibited conformation. Distinct from the canonical AAA+ proteins, the HerA hexamer in this antiphage system adopts a split spiral arrangement, resembling the substrate-binding state, which is stabilized by a unique C-terminal extension. SIR2 and HerA proteins assemble into a [~] 1.1 MDa torch-shaped complex to fight against phage infection. Importantly, disruption of the interactions between SIR2 and HerA largely abolishes the antiphage activity. Interestingly, HerA binding alters the oligomer state of SIR2, switching from a 12-mer state to a 14-mer state. On the other hand, binding of SIR2 stimulates the ATPase activity of HerA. Together, our study not only provides a structural basis for the functional communications between SIR2 and HerA proteins, but also unravels a novel concerted antiviral mechanism through nucleotide (NAD+ and ATP) depletion.

biochemistry↗

bioRxiv2023

Amino acid transporter SLC7A5 regulates Paneth cell function to affect the intestinal inflammatory response

The intestine is critical for not only processing and resorbing nutrients but also protecting the organism from the environment. These functions are mainly carried out by the epithelium, which is constantly being self-renewed. Many genes and pathways can influence intestinal epithelial cell proliferation. Among them is mTORC1, whose activation increases cell proliferation. Here, we report the first intestinal epithelial cell-specific knockout ({Delta}IEC) of an amino acid transporter capable of activating mTORC1. We show that the transporter, SLC7A5, is highly expressed in mouse intestinal crypt and Slc7a5{Delta}IEC reduces mTORC1 signaling. Surprisingly, Slc7a5{Delta}IEC mice have increased cell proliferation but reduced secretory cells, particularly mature Paneth cells. scRNA-seq and electron microscopic analyses revealed dedifferentiation of Paneth cells in Slc7a5{Delta}IEC mice, leading to markedly reduced secretory granules with little effect on Paneth cell number. We further show that Slc7a5{Delta}IEC mice are prone to experimental colitis. Thus, SLC7A5 regulates secretory cell differentiation to affect stem cell niche and/or inflammatory response to regulate cell proliferation.

immunology↗

bioRxiv2020

Functional Interrogation of HOXA9 Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Aberrant HOXA9 expression is a hallmark of most aggressive acute leukemias, including human acute myeloid leukemia (AML) and subtypes of acute lymphoblastic leukemia (ALL). HOXA9 overexpression not only predicts poor diagnosis and outcome but also plays a critical role in leukemia transformation and maintenance. However, our current understanding of HOXA9 regulation in leukemia is limited, hindering development of therapeutic strategies to treat HOXA9-driven leukemia. To mitigate these challenges, we generated the first HOXA9-mCherry knock-in reporter in an MLL-rearranged (MLLr) B-ALL cell line to dissect HOXA9 regulation. By utilizing the reporter and CRISPR/Cas9 mediated screens, we identified transcription factors controlling HOXA9 expression, including a novel regulator, USF2 and its homolog USF1. USF1/USF2 depletion significantly down-regulated HOXA9 expression and impaired MLLr leukemia cell proliferation. Ectopic expression of HOXA9-MEIS1 fusion protein rescued the impaired leukemia cell proliferation upon USF2 loss. Cut&Run analysis revealed the direct occupancy of USF2 onto HOXA9 promoter in MLLr leukemia cells. Collectively, the HOXA9 reporter facilitated the functional interrogation of the HOXA9 regulome and has advanced our understanding of the molecular regulation network in HOXA9-driven leukemia.

cancer biology↗

bioRxiv2020

Modeling the Degradation Effects of AutophagosomeTethering Compounds (ATTEC)

Autophagy is a powerful protein degradation pathway with limited specificity. Our recent study proposed and demonstrated a potential strategy to harness autophagy to selectively degrade a specific pathogenic protein using autophagosome tethering compounds (ATTEC). ATTEC interact with both the target protein and the autophagosome protein LC3, and thus tether the target protein to the autophagosomes for subsequent degradation. The concentration-dependent curve of the target protein is U-shaped, but there has been lack of both kinetic and steady-state modeling of the degradation effects of ATTEC. Here we established a simplified model describing the kinetics and steady-state level of target protein, and characterized how compounds properties, especially binding affinities to LC3 and to the target protein, may influence their degradation effects.

cell biology↗

bioRxiv2019

Structural basis for EPC1-mediated recruitment of MBTD1 into the NuA4/TIP60 acetyltransferase complex

MBTD1, a H4K20me reader, has recently been identified as a component of the NuA4/TIP60 acetyltransferase complex, regulating gene expression and DNA repair. NuA4/TIP60 inhibits 53BP1 binding to chromatin through recognition of the H4K20me mark by MBTD1 and acetylation of H2AK15, blocking the ubiquitination mark required for 53BP1 localization at DNA breaks. The NuA4/TIP60 non-catalytic subunit EPC1 enlists MBTD1 into the complex, but the detailed molecular mechanism remains incompletely explored. Here, we present the crystal structure of the MBTD1-EPC1 complex, revealing a hydrophobic C-terminal fragment of EPC1 engaging the MBT repeats of MBTD1 in a site distinct from the H4K20me binding site. Different cellular assays validate the physiological significance of the key residues involved in the MBTD1-EPC1 interaction. Our study provides a structural framework for understanding the mechanism by which MBTD1 recruits the NuA4/TIP60 acetyltransferase complex to influence transcription and DNA repair pathway choice.

biochemistry↗