Biology subjects

Pan, H.

Publications and source records attributed to Pan, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Systemic delivery of murine SOD2 mRNA to experimental abdominal aortic aneurysm mitigates expansion and rupture

BackgroundOxidative stress is implicated in the pathogenesis and progression of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest although clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient antioxidant levels at the site of AAA. We posit that nanoparticle-based approaches hold promise to overcome challenges associated with systemic administration of antioxidants. MethodsWe employed a peptide-based nanoplatform to overexpress a key modulator of oxidative stress, superoxide dismutase 2 (SOD2). The efficacy of systemic delivery of SOD2 mRNA as a nanotherapeutic agent was studied in two different murine AAA models. Unbiased mass spectrometry-enabled proteomics and high-dimensional bioinformatics were used to examine pathways modulated by SOD2 overexpression. ResultsThe murine SOD2 mRNA sequence was mixed with p5RHH, an amphipathic peptide capable of delivering nucleic acids in vivo to form self-assembled nanoparticles of [~]55 nm in diameter. We further demonstrated that the nanoparticle was stable and functional up to four weeks following self-assembly when coated with hyaluronic acid. Delivery of SOD2 mRNA mitigated the expansion of small AAA and largely prevented rupture. Mitigation of AAA was accompanied by enhanced SOD2 protein expression in aortic wall tissue. Concomitant suppression of nitric oxide, inducible nitric oxide synthase expression, and cell death was observed. Proteomic profiling of AAA tissues suggests that SOD2 overexpression augments levels of microRNAs that regulate vascular inflammation and cell apoptosis, inhibits platelet activation/aggregation, and downregulates mitogen-activated protein kinase signaling. Gene set enrichment analysis shows that SOD2 mRNA delivery is associated with activation of oxidative phosphorylation, lipid metabolism, respiratory electron transportation, and tricarboxylic acid cycle pathways. ConclusionsThese results confirm that SOD2 is key modulator of oxidative stress in AAA. This nanotherapeutic mRNA delivery approach may find translational application in the medical management of small AAA and the prevention of AAA rupture.

cell biology↗

bioRxiv2024

H2A.Z deposition at meiotic prophase I underlies homologous recombination and pachytene genome activation during male meiosis

Accurate meiotic progression is important for gamete formation and the generation of genetic diversity. However, little is known about the identity of chromatin regulators that underlie mammalian meiosis in vivo. Here, we identify the multifaceted functions of the chromatin remodeler ZNHIT1 in governing meiosis. The expression of Znhit1 gradually increases during the meiotic prophase, and Znhit1 knockout in spermatocytes results in arrested pachytene development, impaired DNA double-strand break repair, and defective homologous recombination. Single-cell RNA sequencing and transcriptome analysis reveal that Znhit1 loss dysregulates meiotic transcriptional programs at the pachytene stage. Chromatin immunoprecipitation data show that ZNHIT1 is needed for the incorporation of the histone variant H2A.Z into pachytene chromatin. Moreover, we found that H2A.Z cooperates with the transcription factor A-MYB to co-bind DNA elements and control gene activity. Our findings provide insights into the regulatory mechanisms governing meiotic progression and highlight ZNHIT1 as a critical regulator of meiotic progression.

developmental biology↗

bioRxiv2024

Exploration of the link between COVID-19 and gastric cancer from the perspective of bioinformatics and systems biology

BackgroundCoronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused a global pandemic. Gastric cancer (GC) poses a great threat to peoples health, which is a high- risk factor for COVID-19. Previous studies have found some associations between GC and COVID-19, whereas the underlying molecular mechanisms are not well understood. MethodsWe used a bioinformatics and systems biology approach to investigate the relationship between GC and COVID-19. The gene expression profiles of COVID-19 (GSE196822) and GC (GSE179252) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the shared differentially expressed genes (DEGs) for GC and COVID-19, functional annotation, protein-protein interaction (PPI) network, hub genes, transcriptional regulatory networks and candidate drugs were analyzed. ResultsA total of 209 shared DEGs were identified to explore the linkages between COVID-19 and GC. Functional analyses showed that Immune-related pathway collectively participated in the development and progression of COVID-19 and GC. In addition, there are selected 10 hub genes including CDK1, KIF20A, TPX2, UBE2C, HJURP, CENPA, PLK1, MKI67, IFI6, and IFIT2. The transcription factor/gene and miRNA/gene interaction networks identified 38 transcription factors (TFs) and 234 miRNAs. More importantly, we identified ten potential therapeutic agents, including ciclopirox, resveratrol, etoposide, methotrexate, trifluridine, enterolactone, troglitazone, calcitriol, dasatinib and deferoxamine, some of which have been reported to improve and treat GC and COVID-19. This study also provides insight into the diseases most associated with mutual DEGs, which may provide new ideas for research on the treatment of COVID-19. ConclusionsThis research has the possibility to be contributed to effective therapeutic in COVID-19 and GC.

bioinformatics↗

bioRxiv2024

ADAMTS7 Promotes Smooth Muscle Cell Foam Cell Expansion in Atherosclerosis

Human genetic studies have repeatedly associated ADAMTS7 with atherosclerotic cardiovascular disease. Subsequent investigations in mice demonstrated that ADAMTS7 is proatherogenic and induced in response to vascular injury. However, the cell-specific mechanisms governing ADAMTS7 proatherogenicity remain unclear. To determine which vascular cell types express ADAMTS7, we interrogated single-cell RNA sequencing of human carotid atherosclerosis and found ADAMTS7 expression in smooth muscle cells (SMCs), endothelial cells (ECs), and fibroblasts. We subsequently created SMC- and EC-specific Adamts7 conditional knockout and transgenic mice. Conditional knockout of Adamts7 in either cell type does not reduce atherosclerosis, whereas transgenic induction in either cell type increases atherosclerosis. In SMC transgenic mice, this increase coincides with an expansion of lipid-laden SMC foam cells and a decrease in fibrous cap formation. RNA-sequencing in Adamts7 overexpressing SMCs revealed an upregulation of lipid genes typically assigned to macrophages. Mechanistically, ADAMTS7 increases SMC oxLDL uptake through CD36, whose expression is upregulated by PU.1. ATAC-seq and motif analysis revealed increased chromatin accessibility at AP-1 enriched regions, consistent with AP-1 dependent remodeling of PU.1-regulated lipid-handling loci. In summary, ADAMTS7 promotes atherosclerosis by driving SMC foam cell formation through an AP-1/PU.1/CD36 regulatory axis.

pathology↗

bioRxiv2024

Single-cell multimodal profiling of monocytes reveals diverse phenotypes and alterations linked to cardiovascular disease risks

Monocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. The Cell surface expression of CD14 and CD16 has historically identified them, however, recent single-cell studies have uncovered that they are much more heterogeneous than previously realized. We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) to describe the comprehensive transcriptional and phenotypic landscape of 437,126 monocytes. This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCIIhi, monocyte-platelet aggregates, and non-classical, as well as several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII+CD275+ MHCIIhi, CD42b+ monocyte-platelet aggregates, CD16+CD99- non-classical monocytes, and CD99+ classical monocytes. Each subpopulation exhibited unique functions, developmental trajectories, transcriptional regulation, and tissue distribution. Moreover, we revealed alterations associated with cardiovascular disease (CVD) risk factors, including race, smoking, and hyperlipidemia, and the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol. This integrative and cross-species comparative analysis provides a unique resource to compare alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in CVD and the potential for targeted therapies. SummaryMultimodal profiling provides a comprehensive phenotypic and transcriptional understanding of monocytes in health and cardiovascular disease risk states.

genomics↗

bioRxiv2023

Replication-driven HBV cccDNA loss in chimeric mice with humanized livers

Hepatitis B virus (HBV) infection is largely noncytopathic and requires the establishment of covalently closed circular DNA (cccDNA), which is considered stable in the nuclei of infected cells. Although challenging, approaches to directly target cccDNA molecules or kill infected cells are recommended to eliminate cccDNA. Herein, cccDNA levels were investigated in HBV-infected chimeric mice with humanized livers. HBV-infected cells support robust replication, progressively retain viral products, and head for cytopathic destruction and cccDNA loss. It is difficult for infected cells to retain cccDNA and remain noncytopathic. Replication-driven cccDNA loss is observed at both phases of spread of and persistent infection. The cccDNA replenishment is required to compensate for cccDNA loss. Blocking cccDNA replenishment pathways reduces cccDNA levels by >100-fold. These results prove an unconventional cccDNA elimination strategy that does not directly target cccDNA but aims to transform spontaneous cccDNA loss into progressive cccDNA elimination by blocking cccDNA replenishment.

microbiology↗

bioRxiv2023

Spatially resolved molecular and cellular atlas of the mouse brain

A comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding function of the brain. Here, using snRNA-seq and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters with single-cell resolution involving over 6 million cells as well as for 29,655 genes. We have identified new astrocyte clusters, and demonstrated that distinct cell clusters exhibit preference for cortical subregions. In addition, we identified 155 genes exhibiting regional specificity in the brainstem, and 513 long non-coding RNA exhibited regional specificity in the adult brain. Parcellation of brain regions based on spatial transcriptomic information showed large overlap with that by traditional method. Furthermore, we have uncovered 411 transcription factor regulons with spatiotemporal specificity during development. Thus, our study has discovered genes and regulon with spatiotemporal specificity, and provided a high-resolution spatial transcriptomic atlas of the mouse brain.

neuroscience↗

bioRxiv2023

De novo Design of Peptides that Bind Specific Conformers of α-Synuclein

Insoluble amyloids rich in cross-{beta} fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloid in a conformationally specific manner are lacking. We introduce a novel computational method for de novo design of peptides that tile the surface of -synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a "target backbone" for the design of a peptide binder. Next, we interrogate structures in the PDB database with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of -synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by -synuclein, tau, or A{beta}40. This designed peptide also markedly slowed the formation of -synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.

biophysics↗

bioRxiv2023

Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion

Pancreatic {beta}-cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair {beta}-cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion are similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on {beta}-cell mRNA translation. Prior to induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also of mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex-vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our findings uncover a translational regulatory circuit during {beta}-cell glucose toxicity that impairs expression of proteins with critical roles in {beta}-cell function.

cell biology↗

bioRxiv2023

Bio-inspired mineralization collagen induce fibrocartilage regeneration after tendon-bone injury by activating Gli1+Dkk3+ progenitor cells

A fibrocartilaginous connection between the tendon and bone, plays a critical role in transferring force from muscle to bone to enable joint movement. However, due to the high mechanical stress it experiences, the enthesis is vulnerable to injury and incapable of regenerating. The spatial relationship and functional basis of the principal components of the fibrocartilage - mineral and collagen - have not been clearly elucidated, which is a significant remaining gap in reconstructing complex architectures for promoting interface tissue regeneration. Here, using three-dimensional electron tomography imaging and high-resolution two-dimensional electron microscopy, we discover that mineral particles form a continuous cross-fibrillar phase within the fibrocartilage region. By developing a "floating mineralization" system, we fabricate a three-layer hydrogel that mimics the hierarchical nano- to micro-scale structure of tendon-bone interface (TBI). The middle layer is noteworthy for its resemblance to the nanostructure of fibrocartilage and its superior ability to induce mineralized fibrochondrogenesis in vitro. Based on motor function analysis, imaging diagnosis, histological staining, immunofluorescence staining, and biomechanics performance, we demonstrate that in situ transplantation of the gradient hydrogel achieved tendon-fibrocartilage-bone synchronous regeneration and result in 68% maximum mechanical recovery at 8-week postoperation. Single-cell RNA sequencing analysis reveals that a unique atlas of in situ stem/progenitor cells is generated during the TBI healing in vivo. Notably, the bio-inspired hydrogel microenvironment drived endogenous Gli1+Dkk3+ progenitor cells, playing a key role in TBI regeneration. Therefore, we have successfully decoded and reconstructed the nanostructure of fibrocartilage, which has great potential in TBI regeneration.

bioengineering↗

bioRxiv2023

Hopanoid lipids promote soybean-Bradyrhizobium symbiosis

The symbioses between leguminous plants and nitrogen-fixing bacteria known as rhizobia are well known for promoting plant growth and sustainably increasing soil nitrogen. Recent evidence indicates that hopanoids, a family of steroid-like lipids, promote Bradyrhizobium symbioses with tropical legumes. To characterize hopanoids in Bradyrhizobium symbiosis with soybean, the most economically significant Bradyrhizobium host, we validated a recently published cumate-inducible hopanoid mutant of Bradyrhizobium diazoefficiens USDA110, Pcu-shc::{Delta}shc. GC-MS analysis showed that this strain does not produce hopanoids without cumate induction, and under this condition, is impaired in growth in rich medium and under osmotic, temperature, and pH stress. In planta, Pcu-shc::{Delta}shc is an inefficient soybean symbiont with significantly lower rates of nitrogen fixation and low survival within host tissue. RNA-seq revealed that hopanoid loss reduces expression of flagellar motility and chemotaxis-related genes, further confirmed by swim plate assays, and enhances expression of genes related to nitrogen metabolism and protein secretion. These results suggest that hopanoids provide a significant fitness advantage to B. diazoefficiens in legume hosts and provide a foundation for future mechanistic studies of hopanoid function in protein secretion and motility. IMPORTANCEA major problem for global sustainability is feeding our exponentially growing human population while available arable land is decreasing, especially in areas with the greatest population growth. Harnessing the power of plant-beneficial microbes has gained attention as a potential solution, including the increasing our reliance on the symbioses of leguminous plants and nitrogen-fixing rhizobia. This study examines the role of hopanoid lipids in the symbiosis between Bradyrhizobium diazoefficiens USDA110, an important commercial inoculant strain, and its economically important host soybean. Our research extends our knowledge of the functions of bacterial lipids in symbiosis to an agricultural context, which may one day help improve the practical applications of plant-beneficial microbes in agriculture.

microbiology↗

bioRxiv2023

The crystal structure of bacteriophage lambda RexA provides novel insights into the DNA binding properties of Rex-like phage exclusion proteins

RexA and RexB function as an exclusion system that prevents bacteriophage T4rII mutants from growing on E. coli {lambda} phage lysogens. Recent data established that RexA is a non-specific DNA binding protein that can act independently of RexB to bias the {lambda} bistable switch toward the lytic state, preventing conversion back to lysogeny. The molecular interactions underlying these activities are unknown, owing in part to a dearth of structural information. Here we present the 2.05-[A] crystal structure of the {lambda} RexA dimer, which reveals a two-domain architecture with unexpected structural homology to the recombination-associated protein RdgC. Modelling suggests that our structure adopts a closed conformation and would require significant domain rearrangements to facilitate DNA binding. Mutagenesis coupled with electromobility shift assays, limited proteolysis, and double electron-electron spin resonance spectroscopy support a DNA-dependent conformational change. In vivo phenotypes of RexA mutants suggest that DNA binding is not a strict requirement for phage exclusion but may directly contribute to modulation of the bistable switch. We further demonstrate that RexA homologs from other temperate phages also dimerize and bind DNA in vitro. Collectively, these findings advance our mechanistic understanding of Rex functions and provide new evolutionary insights into different aspects of phage biology.

microbiology↗

bioRxiv2023

Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow

Ectopic bone marrow adipocytes (BMAds) accumulation occurring under diverse pathophysiological conditions leads to bone deterioration. Estrogen-related receptor (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency rescues osteogenesis and vascular formation in adipocyte-rich bone marrow due to estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); and positively modulates Leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased LEPTIN secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/552932v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1132da3org.highwire.dtl.DTLVardef@19342aorg.highwire.dtl.DTLVardef@afe8d7org.highwire.dtl.DTLVardef@dfb1f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Proguanil and chlorhexidine augment the antibacterial activities of clarithromycin and rifampicin against Acinetobacter baumannii

The emergence of Acinetobacter baumannii infections as a significant healthcare concern in hospital settings, coupled with their association with poorer clinical outcomes, has prompted extensive investigation into novel therapeutic agents and innovative treatment strategies. Proguanil and chlorhexidine, both categorized as biguanide compounds, have displayed clinical efficacy as antimalarial and topical antibacterial agents, respectively. In this study, we conducted an investigation to assess the effectiveness of combining proguanil and chlorhexidine with clarithromycin or rifampicin against both laboratory strains and clinical isolates of A. baumannii. The combination therapy demonstrated rapid bactericidal activity against planktonic multidrug-resistant A. baumannii, exhibiting efficacy in eradicating mature biofilms and impeding the development of antibiotic resistance in vitro. Additionally, when administered in conjunction with clarithromycin or rifampicin, proguanil enhanced the survival rate of mice afflicted with intraperitoneal A. baumannii infections, and chlorhexidine expedited wound healing in mice with skin infections. These findings are likely attributable to the disruption of A. baumannii cell membrane integrity by proguanil and chlorhexidine, resulting in heightened membrane permeability and enhanced intracellular accumulation of clarithromycin and rifampicin. Overall, this study underscores the potential of employing proguanil and chlorhexidine in combination with specific antibiotics to effectively combat A. baumannii infections and improve treatment outcomes in clinically challenging scenarios. IMPORTANCEA. baumannii has emerged as a globally significant nosocomial pathogen due to its remarkable ability to acquire antibiotic resistance and develop biofilms on both biotic and abiotic surfaces. Recent research has demonstrated that the antidiabetic drug metformin has a potentiation effect on doxycycline and minocycline against certain multidrug-resistant bacterial pathogens, suggesting the potential of this biguanide agent as a novel tetracyclines adjuvant. In this study, we provide evidence showing that the combination of proguanil and chlorhexidine with clarithromycin or rifampicin exhibits rapid bactericidal activities against both planktonic cells and mature biofilms of A. baumannii, the capacity to inhibit the development of antibiotic resistance and improvement of the treatment outcomes in A. baumannii-infected mice. Given the advantages of repurposing non-antibiotic drugs as antibiotic adjuvants, proguanil and chlorhexidine show promise as adjuvants of specific antibiotics in combating clinically significant pathogenic A. baumannii.

microbiology↗

bioRxiv2023

ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes

Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from a cohort of 83 people and test which lipids association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME both replicably inversely associate with BMI and mechanistically activate calcium fluxes in mouse brown and white adipocytes in vitro, which implicates this pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

bioinformatics↗

bioRxiv2023

Systematic single-cell analysis reveals dynamic control of transposable element activity orchestrating the endothelial-to-hematopoietic transition

BackgroundThe endothelial-to-hematopoietic transition (EHT) process during definitive hematopoiesis in vertebrate is highly conserved. Stage-specific expression of transposable elements (TEs) has been detected during zebrafish EHT and may promote hematopoietic stem cell formation by activating inflammatory signaling. However, little is known about how TEs contribute to the EHT process in human and mouse. ResultsWe reconstructed the single-cell EHT trajectories of human and mouse, and resolved the dynamic expression patterns of TEs during EHT. Most TEs presented a transient co-upregulation pattern along the conserved EHT trajectories. Enhanced TE activation was tightly associated with the temporal relaxation of epigenetic silencing systems. TE products can be sensed by multiple pattern recognition receptors, triggering inflammatory signaling to facilitate the emergence of hematopoietic stem cells. Furthermore, we observed that hypoxia-related signals were enriched in cells with higher TE expression. Additionally, we constructed the hematopoietic cis-regulatory network of accessible TEs and identified potential enhancers derived by TEs, which may boost the expression of specific EHT marker genes. ConclusionsOur study provides a systematic vision on how TEs are dynamically controlled to promote the hematopoietic fate decision through transcriptional and cis-regulatory networks, and pre-train the immunity of nascent hematopoietic stem cells.

bioinformatics↗

bioRxiv2023

Phosphorylation of 53BP1 by ATM enforce neurodevelopmental programs in cortical organoids

53BP1 is a well-established DNA damage repair factor recently shown to regulate gene expression and critically influence tumor suppression and neural development. For gene regulation, how 53BP1 is regulated remains unclear. Here, we showed that 53BP1-serine 25 phosphorylation by ATM is required for neural progenitor cell proliferation and neuronal differentiation in cortical organoids. 53BP1-serine 25 phosphorylation dynamics controls 53BP1 target genes for neuronal differentiation and function, cellular response to stress, and apoptosis. Beyond 53BP1, ATM is required for phosphorylation of factors in neuronal differentiation, cytoskeleton, p53 regulation, and ATM, BNDF, and WNT signaling pathways for cortical organoid differentiation. Overall, our data suggest that 53BP1 and ATM control key genetic programs required for human cortical development.

developmental biology↗

bioRxiv2023

Atherosclerosis is a smooth muscle cell-driven tumor-like disease

Atherosclerosis, the leading cause of cardiovascular disease, is a chronic inflammatory disease involving pathological activation of multiple cell types, such as immunocytes (e.g., macrophage, T cells), smooth muscle cells (SMCs), and endothelial cells. Multiple lines of evidence have suggested that SMC "phenotypic switching" plays a central role in atherosclerosis development and complications. Yet, SMC roles and mechanisms underlying the disease pathogenesis are poorly understood. Here, employing SMC lineage tracing mice, comprehensive molecular, cellular, histological, and computational profiling, coupled to genetic and pharmacological studies, we reveal that atherosclerosis, in terms of SMC behaviors, share extensive commonalities with tumors. SMC-derived cells in the disease show multiple characteristics of tumor cell biology, including genomic instability, replicative immortality, malignant proliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. SMC-specific expression of oncogenic KrasG12D accelerates SMC phenotypic switching and exacerbates atherosclerosis. Moreover, we present a proof of concept showing that niraparib, an anti-cancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. Our work provides systematic evidence that atherosclerosis is a tumor-like disease, deepening the understanding of its pathogenesis and opening prospects for novel precision molecular strategies to prevent and treat atherosclerotic cardiovascular disease.

cell biology↗