Biology subjects

li, Y.

Publications and source records attributed to li, Y..

4 recordsLinked to original sources

bioRxiv2026

A CSF Proteomic Clock Reveals Opposing Brain-Aging Programs and Predicts Neurological Disease Progression

Aging is the risk factor for neurological disease, yet the molecular architecture of human brain aging remains poorly defined. Here, we analyzed more than 10,000 cerebrospinal fluid (CSF) proteomes across multiple cohorts and proteomic platforms to developed a 249-protein CSF aging clock that accurately predicts age and generalizes across independent datasets. CSF brain-age acceleration was increased across diverse neurological diseases, associated with blood-brain barrier (BBB) dysfunction, and predictive of longitudinal cognitive decline, neuroimaging progression, and dementia conversion. A simplified 30-protein panel retained similar prognostic performance. Biologically, clock proteins resolved two opposing programs: pro-aging activation of immune, vascular/BBB, ECM and coagulation pathways marked by CHI3L1, CD14, VWF, LRG1 and LTBP2, and anti-aging collapse of neuronal, synaptic, axonal and structural-maintenance programs marked by NPTX2, COL1A2, NID1, CDH8 and PENK. Brain-wide single-cell and regional mapping linked these programs to disease-vulnerable compartments. These findings establish a molecular framework for biological brain aging and neurological disease vulnerability.

neuroscience↗

bioRxiv2026

Histone modifications analysis reveals enhancers reprogramming during maternal-to-zygotic transition

Enhancers are important epigenetic regulatory components that coordinate spatiotemporal gene expression and play a crucial role in mammalian development, gene regulation, and illness. During early mammalian embryogenesis, histone modifications including H3K4me1, a canonical enhancer mark, and H3K27ac, which identifies active enhancers, are still poorly understood. This study profiles the genome-wide H3K4me1 and H3K27ac patterns in mouse oocytes and pre-implantation embryos using low-input CUT&RUN (cleavage under targets and release using nuclease) with input as low as 50 cells. Both markers are enriched in distal regions and exhibit distinct sequence preferences and reprogramming dynamics in pre-implantation embryos. H3K27ac, a mark of active enhancers, is reprogrammed at the 2-cell stage, whereas H3K4me1 is remodeled at the 4-cell stage and overlaps with H3K27ac, coinciding with accessible chromatin regions. Interestingly, H3K4me1 and H3K27ac are co-localized in promoter regions, where they are mutually exclusive to H3K4me3. Enhancers are dynamically remodeled during maternal-to-zygotic transition (MZT). there are three enhancer types: active enhancers (H3K4me1/H3K27ac), primed enhancers (H3K4me1), and poised enhancers (H3K4me1/H3K27me3). Active enhancers increase significantly after zygotic genome activation. Further, super-enhancers are present across the genome and are mainly enriched in promoters. The specific motifs enriched by super-enhancers may be associated with the variations of gene expressions at different stages.

developmental biology↗

bioRxiv2023

Cryo-EM structure of DNA polymerase θ helicase domain in complex with inhibitor novobiocin

DNA double-strand breaks (DSBs) are highly toxic lesions that occur during the cellular metabolic process. DNA Polymerase theta (Pol{theta}) is an error-prone polymerase that has been implicated in the repair of chromosome breaks, recovery of broken replication forks, and translesion synthesis. The inhibition of Pol{theta} activity has been implicated in killing HR-deficient tumor cells in vitro and in vivo. We present the first biochemical evidence that the antibiotics novobiocin (NVB) noncompetitively inhibit ATP hydrolysis by the ATPase domain of the Pol{theta} helicase domain (Pol{theta}-HLD). We report the Cryo-EM structure of apo dimeric Pol{theta} helicase domain (Pol{theta}-HLD), and the first inhibitor occupied Pol{theta}-HLD structure. Our structure identifies a non-canonical novobiocin binding pocket, distinct from the canonical site that partially overlaps with the ATP in the ATPase domain. Comparison with the homolog helicase Hel308-DNA duplex complex suggests that the novobiocin competitively binds to a triangle hub on the DNA translocation pathway and blocks the ssDNA binding and translocation. Furthermore, the first dimeric structure of Pol{theta}-HLD also provides a structural framework for revealing the microhomology-mediated end-joining mechanism. Our results demonstrate that the inhibitor-occupied structure combined with rational, structure-based drug design will undoubtedly accelerate the discovery of potent inhibitors with better efficacy and target selectivity to human Pol{theta}.

biochemistry↗

bioRxiv2020

m6A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes

N6-methyladenosine (m6A) RNA methylation is one of the most abundant modifications on mRNAs and plays an important role in various biological processes. The formation of m6A is catalysed by a methyltransferase complex containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m6A modification in liver lipid and glucose metabolism remain unclear. Here, we show that both Mettl3 expression and m6A level increased in the liver of mice with High Fat Diet (HFD)-induced metabolic disorders, and overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. Hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m6A loss causes extended RNA half-lives of metabolism-related genes, consequently protects mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m6A in HFD-induced metabolic disorders and hepatogenous diabetes.

genetics↗