Biology subjects

Du, Q.

Publications and source records attributed to Du, Q..

At least 19 recordsLinked to original sources

bioRxiv2026

Atypical Chemokine Receptor DARC/ACKR1 Is Expressed Selectively by Neurons with Regional Heterogeneity and Protects against Neuroinflammation and Cognitive Impairment

Atypical chemokine receptors (ACKRs) regulate inflammatory responses by scavenging and sequestering chemokines. The Duffy antigen receptor for chemokines (DARC), also known as ACKR1, binds multiple inflammatory chemokines and regulates inflammation in peripheral tissues. However, the distribution and functional role of DARC/ACKR1 in the brain remain to be defined. Here, we show that DARC/ACKR1 is widely expressed throughout the mouse brain, with marked regional heterogeneity. DARC/ACKR1 is predominantly expressed by neurons and is not detected in microglia or astrocytes. Importantly, this neuronal expression pattern was also observed in the human brain. Furthermore, DARC/ACKR1 deficiency resulted in enhanced neuroinflammation, characterized by increased microglial activation and astrogliosis across multiple brain regions, particularly the hippocampus, and was accompanied by cognitive deficits. Together, these findings identify DARC/ACKR1 as a previously unrecognized neuron-specific atypical chemokine receptor that plays an important role in restraining neuroinflammation and preserving cognitive function.

neuroscience↗

bioRxiv2026

CREPAS: a reproducible nascent chromatin sequencing analysis pipeline for epigenome replication studies

Chromatin-based genomics data are essential for understanding genome regulation and the mechanisms underlying epigenetic memory. Recent methods such as ChOR-seq and SCAR-seq assess histone modifications and chromatin-associated proteins during and after replication, capturing chromatin states that contribute to memory across cell divisions. Current tools for chromatin data analysis lack scalability and reproducibility across computing infrastructures, offer limited parameters, and are applicable only to a few sequencing techniques, ignoring the information from nascent chromatin assays. To address these challenges, we developed CREPAS, a Nextflow pipeline for analyzing nascent and parental chromatin sequencing data, including ChIP-seq, ChOR-seq, SCAR-seq, OK-seq, ATAC-seq, CUT&RUN, and CUT&Tag, and derivative protocols. CREPAS provides an end-to-end solution, from quality control to advanced analyses, including downsampling, peak calling, annotation, and visualization. By harnessing quantitative assays such as qChIP-seq and qChOR-seq, the normalization methods in CREPAS allow to compare the restoration kinetics of individual marks or proteins across replication timepoints. Moreover, the pipeline includes calculations such as fork directionality and partitioning using OK-seq and SCAR-seq data, linking replication dynamics to epigenetic inheritance. CREPAS is a valuable resource that enhances the efficiency and reproducibility of nascent chromatin sequencing data analyses, enabling the study of chromatin replication and propagation of epigenetic states. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/732899v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@11634b8org.highwire.dtl.DTLVardef@df2e07org.highwire.dtl.DTLVardef@46d117org.highwire.dtl.DTLVardef@14950a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2026

Chronic Mild Stress Impairs Hippocampal Myelination through SOX6-Dependent Dysfunction of Oligodendrocyte Lineage Cells

Chronic stress induces structural and functional changes in the brain, increasing susceptibility to major depressive disorder and other mental illnesses. Myelination deficits are a key pathological feature of stress-related disorders, yet the molecular mechanisms linking chronic stress to oligodendrocyte dysfunction remain poorly understood. Here, we used single-nucleus multiome sequencing to map gene expression and chromatin-accessibility remodeling in the hippocampus of mice exposed to chronic unpredictable mild stress (CUMS), a model that simulates key features of human daily stressors. CUMS induced broad molecular reprogramming across hippocampal cell populations, with stress-responsive gene networks significantly enriched for depression-associated genes. The oligodendrocyte lineage showed heightened vulnerability, with CUMS preferentially disrupting immature OPC/intermediate states and impairing OPC migration, OPC-to-ODC lineage progression, intercellular communication, and myelination. Integrated multiomic analysis identified stage-specific cis-regulatory elements and stress-sensitive gene regulatory networks, converging on SOXD transcription factors, particularly SOX5 and SOX6, as key regulators of OPC dysfunction. SOX6 ChIP-seq confirmed direct SOX6 binding at regulatory elements associated with genes controlling OPC morphogenesis, migration, and glutamatergic signaling. CUMS reduced SOX6 protein levels and SOX6-associated regulatory network activity in OPCs, whereas OPC-specific enhancer-driven restoration of SOX6 rescued stress-induced defects in OPC migration and myelination. Together, these findings define a stress-sensitive SOXD/SOX6 regulatory mechanism linking chronic stress to oligodendrocyte lineage dysfunction and myelination deficits, identifying SOX6 as a functional regulatory node with therapeutic potential for stress-related brain pathology.

neuroscience↗

bioRxiv2026

Activation of DMH GABAergic neurons, but not local GABAergic AgRP neurons, attenuates chronic stress-induced POMC neuron hyperactivity

Identifying the neural circuits engaged and reshaped by chronic stress is critical for understanding how adaptive responses shift to maladaptive behaviors that contribute to stress-related disorders. Our previous work demonstrates that chronic unpredictable stress (CUS) induces a persistent increase in the firing activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC). This hyperactivity is due, in part, to a reduction in GABAergic synaptic transmission onto POMC neurons, indicating a disruption in inhibitory control. However, the sources of GABAergic inputs responsible for this effect of chronic stress are unknown. Although AgRP neurons provide local GABAergic input onto POMC neurons and are suppressed by chronic stress, chemogenetic activation of AgRP neurons during stress exposure failed to reduce POMC neuron hyperactivity. GABAergic projections originating from the dorsomedial hypothalamus (DMH) represent another source of inhibitory input to POMC neurons. We found that CUS decreased the firing activity of DMH GABAergic neurons with sex differences, with females exhibiting greater vulnerability to stress-induced suppression. Chemogenetic activation of these neurons during chronic stress markedly attenuated POMC neuron hyperactivity in both sexes, indicating that DMH GABAergic neurons function as a critical upstream regulator of POMC neuron activity under chronic stress. These findings suggest that reduced inhibitory input from DMH GABAergic neurons, rather than local GABAergic AgRP neurons, drives POMC neuron hyperactivity. The weakening of the DMHGABA[->]ARCPOMC circuit activity may represent a novel mechanism underlying maladaptive stress responses and a potential therapeutic target for stress-related disorders.

neuroscience↗

bioRxiv2026

Coronavirus envelope protein drives iron sensing disorder by hijacking the TAp73-FDXR axis

Iron overload is increasingly recognized as a critical contributor to coronavirus pathogenesis1, yet the underlying induction mechanisms remain unclear. Here, we uncover a fundamental pathway by which coronavirus drives IRP1 RNA-binding activity to induce iron accumulation2 via targeting the TAp73-FDXR axis. Specifically, coronavirus infection represses transcription of FDXR (encoding the key rate-limiting enzyme in host iron-sulfur cluster synthesis3), thereby impairing host iron-sulfur cluster generation to trigger the functional conversion of the cytosolic aconitase 1 (ACO1) into iron-regulatory protein 1 (IRP1)4, ultimately leading to the hosts persistently false perception of iron deficiency. We identify TAp73 as the primary transcription factor governing FDXR expression, and demonstrate that the coronavirus envelope protein (CoV-E) orchestrates TAp73 nuclear export. Subsequently, CoV-E binds TAp73 through a critical valine residue within its C-terminal PBM domain, inducing the K48-linked ubiquitination and proteasomal degradation of TAp73. Furthermore, we developed a CoV-E-targeting molecule, DPTP-FC, which blocks CoV-E-TAp73 interaction via forming steric hindrance and effectively alleviates iron accumulation and tissue damage caused by PEDV, PDCoV, and SARS-CoV-2 infection. Our study reveals the central role of the TAp73-FDXR axis in CoV-induced iron accumulation, highlighting CoV-E as an attractive antiviral target and DPTP-FC as a promising therapeutic candidate.

microbiology↗

bioRxiv2026

Unified function of FACT in mammalian chromatin replication and transcription, dissolving and restoring nucleosomes to counteract genome aggregation

Nucleosomes with their associated modifications underlie genome organisation and regulation. Replication and transcription require nucleosome disassembly to access the DNA template. How this is orchestrated without jeopardizing chromatin function remains unknown. Here, we reveal a general, global requirement of the histone chaperone FACT in mammalian replication, transcription and chromatin maintenance. Upon acute FACT depletion, replisome and RNA polymerase progression is halted genome-wide and chromatin structure in their wake collapses with reduced nucleosome occupancy, irregular spacing and intermediate assemblies. Chromatin states deteriorate as modified histones are lost due to a lack of histone recycling. Chromatin fiber disorder further manifests in the 3D genome, triggering active genes to coalesce in aberrant microcompartments. This establishes a unifying mechanistic basis for mammalian chromatin replication and transcription, with FACT mediating nucleosome disruption and re-assembly and thereby guarding against spurious chromatin aggregation. Nucleosome organization can therefore dynamically regulate genome architecture.

molecular biology↗

bioRxiv2026

Phyllosphere and rhizosphere microbiomes empower Nicotiana tobacum complex traits dissection and prediction

Understanding how plant-associated microbiomes interact with host genome variation to influence agronomic traits is essential for advancing microbiomeassisted crop improvement. In this study, we characterized the phyllosphere and rhizosphere microbiomes of 164 diverse Nicotiana tabacum accessions using 16S rRNA sequencing and integrated these data with host genomic variation and 22 agronomic traits. The two microbiomes exhibited distinct taxonomic structures, diversity patterns, and predicted metabolic functions. Microbiome genomewide association studies identified extensive host genetic control over microbial abundance, including 49 shared genomic loci that explained nearly half of the heritable variation in both microbiomes. Microbiomewide association studies revealed biologically meaningful associations between specific ASVs and agronomic traits. However, network analysis demonstrated that microbial subcommunities, rather than individual taxa, contributed substantially to phenotypic variation. Then, colocalization analysis further identified genetic variants jointly influencing microbial abundance and metabolite traits, highlighting potential host-microbe-trait causal links. Incorporating microbiome data into genomic selection models, we successfully improved prediction accuracy for several traits, especially plant architecture and flowering. Together, this work provides a comprehensive populationlevel framework linking host genetics, microbiome composition, and agronomic traits in tobacco, offering new insights for microbiomeinformed breeding strategies.

plant biology↗

bioRxiv2025

The regulatory landscape of nascent transcription in human health and disease

Transcriptional regulatory elements (TREs) orchestrate gene expression programs fundamental to cellular identity and transitions across physiological and pathological states. Here, we present a high-resolution atlas of RNA Polymerase II-engaged TREs (enhancers and promoters) across all major human organ systems and a broad spectrum of developmental and disease states. This atlas is generated using PRO-cap, a highly sensitive method that detects nascent RNA at transcription initiation sites, a critical feature of active TREs. The base-pair resolution of PRO-cap enables systematic dissection of transcription initiation architecture, revealing associations among tissue specificity, evolutionary constraint, transcription factor usage, and regulatory connectivity. Integration with deep learning models such as ProCapNet further provides a framework for prioritizing noncoding variants from GWAS and eQTL studies. Moreover, this tissue-resolved atlas identifies lineage-specific regulatory programs and their alterations in diseases such as metastatic cancer, where TRE landscapes capture regulatory signatures reflecting both tissue of origin and adaptive responses to distant niches. Together, these findings establish transcription initiation at regulatory elements as a defining and mechanistically informative layer of gene regulation across development, physiology, and disease.

genomics↗

bioRxiv2025

Neuronal HDAC9: A key regulator of cognitive and synaptic aging, rescuing Alzheimer's disease-related phenotypes

Epigenetic regulation is a key determinant of the aging process, and its dysregulation contributes to cognitive aging and increased vulnerability to Alzheimers disease (AD). As major regulators of epigenetic processes, histone deacetylases (HDACs) have emerged as potential therapeutic targets for cognitive enhancement in neurodegenerative diseases. However, the distinct roles of individual HDAC isoforms remain to be defined. Here, we report that HDAC9 is specifically expressed in neurons of human and mouse brains, and its expression declines with age. HDAC9 deficiency impairs cognitive function and synaptic plasticity in young mice. Selective deletion of HDAC9 in hippocampal CA1 neurons also induces cognitive impairment. In contrast, overexpression of HDAC9 in forebrain glutamatergic neurons preserves cognitive function in aged mice. Moreover, HDAC9 is also downregulated in the brain of AD mouse models, whereas neuronal overexpression of HDAC9 alleviates AD-related cognitive and synaptic deficits and reduces A{beta} deposition. Together, these findings suggest neuronal HDAC9 is necessary and sufficient for maintaining cognitive and synaptic functions in the context of aging and AD.

neuroscience↗

bioRxiv2025

Low nucleus to cytoplasmic ratio compromises cytokinesis, genome stability and development in haploid embryonic cells

Mammalian species exist as diploid organisms, with only gametes existing as stable, nonproliferating haploids. Haploid mammalian pluripotent stem cells, in all derived species to date - mouse, human and rat - undergo spontaneous diploidization. Here, we investigated the mechanisms affecting the stability of the haploid state using the mouse and human embryo, as well as a human embryonic stem cells. We demonstrate that diploidization occurs early in preimplantation development and is often unproductive, with haploid embryos exhibiting decreased developmental potential. Haploid embryos show increased chromosome segregation errors at the first mitosis, failure to align chromosomes on the metaphase plate in the second mitosis. Delayed mitotic progression and failure to form a central spindle and a midbody are followed by cytokinesis failure, diploidization, increased DNA damage marked by {gamma}H2AX and RPA32 foci, and low developmental potential. By increasing the nucleo-cytoplasmic ratio in diploids, or reducing this ratio in haploids, these phenotypes can be induced in diploids or reduced in haploids. Changing ploidy alone from haploid to diploid without also adjusting nucleo-cytoplasmic ratio does not improve mitotic phenotypes and developmental outcomes. Thus, the most upstream driver responsible for the instability of the haploid state is a stage- specific ratio of nucleus to cell size.

cell biology↗

bioRxiv2024

Androgen stimulation rapidly reorganizes temporal 3D genome and epigenome states to trigger AR-mediated transcription in prostate cancer.

Androgen receptor (AR)-mediated transcription drives prostate cancer progression and remains a critical therapeutic target. AR activation by androgens triggers nuclear translocation, DNA binding at AR regulatory elements (AREs) and transcription initiation. This process involves co-factors such as FOXA1, epigenetic modifications, and 3D chromatin interactions. However, the temporal coordination of these events during AR-mediated transcription remains poorly understood. Using a time-course androgen stimulation model in prostate cancer cells, we integrated temporal multi-omics data within the MOFA+ framework to dissect AR-mediated transcriptional dynamics. Our analysis revealed that rapid AR binding at gene promoters is crucial for initiating nascent transcription of AR target genes. We identified H3K27 acetylation at flanking AREs, pre-marked by constitutive FOXA1 binding, occurs prior to AR recruitment. Additionally, androgen stimulation induced a temporal early shift in nascent transcription from MYC to AR target genes, associated with transient disruption of 3D chromatin interactions. Finally, we showed that CRISPR-mediated inhibition of AR-associated chromatin contacts suppresses distal linked target genes, demonstrating that dynamic genome architecture is functionally required for AR-driven transcription. Together these findings uncover the dynamic reorganization of 3D chromatin structure and transcription factor binding post-androgen stimulation, resulting in distinct temporal epigenomic states. This work provides new insights into the mechanisms governing AR-mediated transcriptional activation in prostate cancer and highlights the interplay between MYC and AR in regulating transcription in hormone-driven cancers.

genomics↗

bioRxiv2024

Placental and fetal microbiota in rhesus macaque: a case study using metagenomic sequencing

Recent evidence challenging the notion of a sterile intrauterine environment has sparked research into the origins and effects of fetal microbiota on immunity development during gestation. Rhesus macaques (RMs) serve as valuable non-human primate (NHP) models due to their similarities to humans in development, placental structure, and immune response. In this study, metagenomic analysis was applied to the placenta, umbilical cord, spleen, gastrointestinal (GI) tissues of an unborn RM fetus, and the maternal intestine, revealing the diversity and functionality of microbes in these tissues. We observed substantial microbial sharing between the mother and fetus, with the microbial composition of the placenta and umbilical cord more closely resembling that of the fetal organs than the maternal intestine. Notably, compared with other adult RMs, there was a clear convergence between maternal and fetal microbiota, alongside distinct differences between the microbiota of adults and the fetus, which underscores the unique microbial profiles in fetal environments. Furthermore, the fetal microbiota displayed a less developed carbohydrate metabolism capacity than adult RMs. It also shared antibiotic resistance genes (ARGs) with both maternal and adult RM microbiomes, indicating potential vertical transmission. Comparative analysis of the metagenomes between the RM fetus and a human fetus revealed significant differences in microbial composition and genes, yet also showed similarities in certain abundant microbiota. Collectively, our results contribute to a more comprehensive understanding of the intrauterine microbial environment in macaques.

microbiology↗

bioRxiv2024

Phosphorylation-induced flexibility of proto-oncogenic Bcl3 regulates transcriptional activation by NF-κB p52 homodimer

B cell lymphoma 3 (Bcl3), a member of the I{kappa}B family proteins, modulates transcription by primarily associating with NF-{kappa}B p50 and p52 homodimers. Bcl3 undergoes extensive phosphorylation, though the functions of many of these modifications remain unclear. We previously described that phosphorylation at Ser33, Ser114 and Ser446 partially switches Bcl3 from acting as an I{kappa}B-like inhibitor to a transcription regulator by associating with the (p52:p52):DNA binary complex. Here, we identified another critical phosphorylation site, Ser366. Substituting at all four residues to phospho-mimetic glutamate further enhances Bcl3s transcriptional activity. Phospho-modifications retain Bcl3s ability to stably bind p52 but induces reciprocal structural changes as revealed by HDX-MS experiments; the N-terminal region stiffens, while the C-terminus becomes more flexible. The increased flexibility allowed the Bcl3:(p52p52) binary complex to better accommodate DNA. The removal of the C-terminal 28-residues transformed Bcl3 into a transcriptional activator independent of phosphorylation. Notably, most identified mutations in Bcl3 from various cancers map to its C-terminus, suggesting the functional relevance of Bcl3 C-terminal structural flexibility and enhanced interaction with (p52p52):DNA complex to transcriptional potential and disease. Overall, this study uncovers the mechanistic basis by which phosphorylation-driven structural changes convert Bcl3 from an inhibitor to a transcriptional cofactor of NF-{kappa}B, and how deregulation of its activity through altered phosphorylation or mutation can lead to cancer.

biochemistry↗

bioRxiv2024

UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation

The RING E3 ubiquitin ligase UHRF1 is an established cofactor for DNA methylation inheritance. Nucleosomal engagement through histone and DNA interactions directs UHRF1 ubiquitin ligase activity toward lysines on histone H3 tails, creating binding sites for DNMT1 through ubiquitin interacting motifs (UIM1 and UIM2). Here, we profile contributions of UHRF1 and DNMT1 to genome-wide DNA methylation inheritance and dissect specific roles for ubiquitin signaling in this process. We reveal DNA methylation maintenance at low-density CpGs is vulnerable to disruption of UHRF1 ubiquitin ligase activity and DNMT1 ubiquitin reading activity through UIM1. Hypomethylation of low-density CpGs in this manner induces formation of partially methylated domains (PMD), a methylation signature observed across human cancers. Furthermore, disrupting DNMT1 UIM2 function abolishes DNA methylation maintenance. Collectively, we show DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.

genomics↗

bioRxiv2024

SHP2-triggered endothelium activation fuels estradiol-independent endometrial sterile inflammation

Endometrial hyperplasia (EH) is a common gynecological disease primarily driven by excess estrogen. How endometrial sterile inflammation regulates EH remains unclear. First, we found the upregulation of SHP2 in endometrial endothelial cells from patients with EH by scRNA-Seq. SHP2 promoted inflammatory activation of endothelial cells, which promoted macrophage transendothelial migration. Subsequently, IL1{beta} and TNF from macrophages gave a feedforward loop to enhance endothelial cell activation and result in more IGF1 secretion, thereby sustaining sterile endometrial inflammation and facilitating endometrial epithelial cell proliferation even after estradiol withdrawal. Mechanistically, results of bulk RNA-Seq and phosphoproteomic analyses showed that endothelial SHP2 dephosphorylated RIPK1Y380 after estradiol stimulation. This event promoted activator protein 1 (AP-1) activation, instigating inflammation and increased CXCL10, CXCL13, COX2 and IGF1 secretion. Furthermore, targeting SHP2 by SHP099 or endothelial-specific SHP2 deletion alleviated EH progression in mice. Collectively, our findings demonstrate that SHP2 mediates the transition of endothelial activation, from estradiol-driven short inflammation to macrophage-amplified continuous sterile inflammation. Targeting chronic sterile inflammation mediated by endothelial cell activation is a promising strategy for non-hormonal intervention in EH.

molecular biology↗

bioRxiv2023

Permanent Neonatal Diabetes-causing Insulin Mutations have Dominant Effects on Proinsulin Processing and Beta Cell Identity

Heterozygous coding sequence mutations of the INS gene are a cause of permanent neonatal diabetes (PNDM) that results from beta cell failure. We explored the causes of beta cell failure in two PNDM patients with two distinct INS mutations. Using b and mutated hESCs, we detected accumulation of misfolded proinsulin and impaired proinsulin processing in vitro, and a dominant-negative effect of these mutations on the in vivo performance of patient-derived SC-beta cells after transplantation into NSG mice. These insulin mutations derange endoplasmic reticulum (ER) homeostasis, and result in the loss of beta-cell mass and function. In addition to anticipated apoptosis, we found evidence of beta-cell dedifferentiation, characterized by an increase of cells expressing both Nkx6.1 and ALDH1A3, but negative for insulin and glucagon. These results highlight both known and novel mechanisms contributing to the loss and functional failure of human beta cells with specific insulin gene mutations.

cell biology↗

bioRxiv2023

Aberrant activation of the innate immune sensor PKR by self dsRNA is prevented by direct interaction with ADAR1

Loss of dsRNA editing by Adar1 leads to aberrant interferon induction in Adar null mouse embryos. Adar Mavs mutants, in which this interferon induction is prevented, die within two weeks of birth. We show here that early death of pups is reduced in Adar Mavs EIF2k2 (Pkr) mutants, identifying PKR as the second aberrantly activated dsRNA sensor in Adar mutant mice. In intestines of Adar Mavs pups transit amplifying progenitor cells in intestinal crypts die and intestinal villi are lost in pups before death; intestinal defects are prevented in Adar Mavs Eifak2. In human A549 lung cancer cells ADAR1 forms a complex with PKR. AlphaFold modelling predicts a direct inhibitory interaction of ADAR1 dsRBDIII with the PKR near the kinase active site and a new mode for ADAR1 dsRNA-binding. Mutations at residues required for ADAR1 dsRNA binding or for predicted PKR contacts, prevent interaction with PKR.

immunology↗

bioRxiv2023

MicroRNA-375 is induced during astrocyte-to-neuron reprogramming and promotes survival of reprogrammed neurons when overexpressed

While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. MicroRNAs (miRNAs), as post-transcriptional regulators of gene expression, play crucial roles during development and under various pathological conditions. To understand the function of miRNAs during AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activates essential neuronal genes to initiate reprogramming process but also induces miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and are also upregulated by NeuroD1. We further showed that manipulating miR-375 level regulates nELAVLs expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs are also induced by reprogramming factors Neurog2 and ASCL1 in HA suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improves NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA even in cultures treated with the chemotherapy drug Cisplatin. Moreover, miR-375 overexpression doesnt appear to compromise maturation of the reprogrammed neurons in long term HA cultures. Lastly, overexpression of miR-375-refractory ELAVL4 induces apoptosis and reverses the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrate a neuro-protective role of miR-375 during NeuroD1-mediated AtN reprogramming and suggest a strategy of combinatory overexpression of NeuroD1 and miR-375 for improving neuronal reprogramming efficiency.

neuroscience↗