Biology subjects

ZHANG, W.

Publications and source records attributed to ZHANG, W..

5 recordsLinked to original sources

bioRxiv2025

Differential sensitivity to LINE 1-induced damage contributes to the expansion of Tet2-deficient HSCs upon chronic inflammatory stress

Chronic inflammation disrupts hematopoietic stem cell (HSC) function and drives the expansion of TET2-mutated clones, fostering clonal hematopoiesis of indeterminate potential (CHIP). However, the molecular mechanisms linking inflammation to these hematopoietic alterations remain poorly understood. Here, we uncover a pivotal role of transposable element (TE) derepression, specifically of the most recent LINE-1 (L1) elements, in mediating inflammation-induced HSC dysfunction. We show that chronic exposure to low-dose lipopolysaccharide (LPS) causes a loss of the heterochromatin mark H3K9me3 at L1s in wild-type (WT) HSCs, leading to L1 activation, DNA damage, and reduced clonogenic capacity. Remarkably, Tet2-/- HSCs are resistant to this LPS-induced L1 derepression and associated genomic instability. Furthermore, targeted degradation of L1 RNAs in WT HSCs diminishes the competitive advantage of Tet2-/- HSCs under chronic inflammatory conditions both in vitro and in vivo. These findings reveal epigenetic control of L1 elements as a previously unrecognized mechanism that links chronic inflammation to HSC impairment and clonal expansion of Tet2-mutant cells. This work highlights TE regulation as a critical determinant of hematopoietic fitness and clonal evolution under inflammatory stress.

cell biology↗

bioRxiv2024

Orchestrating the Acquisition of Oligodendrocyte Precursor Cell versus Olfactory Bulb Interneuron Fates through Olig1/2 during Mammalian Cortical Gliogenesis and Gliomagenesis

The hijacking of developmental gliogenesis programs is a hallmark of glioblastoma (GBM), in which glial precursor cells (GPCs) typically differentiate into both neurons and glial cells. In GBM, this process is disrupted, leading to the overproduction of proliferative glial-like cells. Our study demonstrates that the knockout of Olig1/2 in both normal development and gliomagenesis causes GPCs to shift from generating highly proliferative oligodendrocyte precursor cells to producing non-proliferative olfactory bulb interneurons. Mechanistically, Olig1/2 play dual roles by orchestrating distinct transcriptional programs in GPCs, particularly inhibiting the expression of Gsx2 through direct binding to its multiple enhancers. Additionally, we provide compelling evidence that human H3.3G34R/V-mutant tumors, a subtype of high-grade gliomas, originate from dorsal cortical-derived GPCs rather than from the previously assumed progenitors in the ventral basal ganglia. Collectively, our findings reveal a previously unrecognized role of Olig1/2 in both gliogenesis and gliomagenesis, offering deeper insights into the connections between normal neural development and tumorigenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/623106v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@10ea118org.highwire.dtl.DTLVardef@1725006org.highwire.dtl.DTLVardef@1e3ce25org.highwire.dtl.DTLVardef@f300ee_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

A Germinal Center Checkpoint of AIRE in B Cells LimitsAntibody Diversification

In response to antigens, B cells undergo antibody diversification, including affinity maturation and class switching, mediated by activation-induced cytidine deaminase (AID) in secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of antibody diversification is of fundamental importance, though the mechanisms underlying these pathways are not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in germinal center (GC) B cells in a CD40-dependent manner, interacts with AID and negatively regulates antibody affinity maturation and class switching by inhibiting AID function. AIRE deficiency in B cells caused altered antibody repertoire, increased somatic hypermutations, elevated autoantibodies to T helper 17 effector cytokines and defective control of skin Candida albicans. These results define a GC B cell checkpoint of humoral immunity and illuminate new approaches of generating high-affinity neutralizing antibodies for immunotherapy.

immunology↗

bioRxiv2021

RNA silencing by CRISPR in plants does not require Cas13

RNA-targeting CRISPR-Cas can provide potential advantages over DNA editing, such as avoiding pleiotropic effects of genome editing, providing precise spatiotemporal regulation and expanded function including anti-viral immunity. Here, we report the use of CRISPR-Cas13 in plants to reduce both viral and endogenous RNA. Unexpectedly, we discovered that crRNA designed to guide Cas13 could, in the absence of the Cas13 protein, cause substantial reduction in RNA levels as well. We demonstrate Cas13-independent guide-induced gene silencing (GIGS) in three plant species, including stable transgenic Arabidopsis. We determined that GIGS utilizes endogenous RNAi machinery despite the fact that crRNA are unlike canonical triggers of RNAi such as miRNA, hairpins or long double-stranded RNA. These results suggest that GIGS offers a novel and flexible approach to RNA reduction with potential benefits over existing technologies for crop improvement. Our results demonstrate that GIGS is active across a range of plant species, evidence similar to recent findings in an insect system, which suggests that GIGS is potentially active across many eukaryotes.

plant biology↗

bioRxiv2018

PIRD: Pan immune repertoire database

MotivationT and B cell receptors (TCRs and BCRs) play a pivotal role in the adaptive immune system by recognizing an enormous variety of external and internal antigens. Understanding these receptors is critical for exploring the process of immunoreaction and exploiting potential applications in immunotherapy and antibody drug design. Although a large number of samples have had their TCR and BCR repertoires sequenced using high-throughput sequencing in recent years, very few databases have been constructed to store these kinds of data. To resolve this issue, we developed a database.\n\nResultsWe developed a database, the Pan Immune Repertoire Database (PIRD), located in China National GeneBank (CNGBdb), to collect and store annotated TCR and BCR sequencing data, including from Homo sapiens and other species. In addition to data storage, PIRD also provides functions of data visualisation and interactive online analysis. Additionally, a manually curated database of TCRs and BCRs targeting known antigens (TBAdb) was also deposited in PIRD.\n\nAvailability and ImplementationPIRD can be freely accessed at https://db.cngb.org/pird.

immunology↗