Biology subjects

Cui, L.

Publications and source records attributed to Cui, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

ROS-induced translational regulation--through spatiotemporal differences in codon recognition--is a key driver of brown adipogenesis

The role of translational regulation in brown adipogenesis is relatively unknown. Localized translation of mRNAs encoding mitochondrial components enables swift mitochondrial responses, but whether this occurs during brown adipogenesis, which involves massive mitochondrial biogenesis, has not been explored. Here, we used ribosome profiling and RNA-Seq, coupled with cellular fractionation, to obtain spatiotemporal insights into translational regulation. During brown adipogenesis, a translation bias towards G/C-ending codons is triggered first in the mitochondrial vicinity by reactive oxygen species (ROS), which later spreads to the rest of the cell. This translation bias is induced through ROS modulating the activity of the tRNA modification enzyme, ELP3. Intriguingly, functionally relevant mRNAs, including those encoding ROS scavengers, benefit from this bias; in so doing, ROS-induced translation bias both fuels differentiation and concurrently minimizes oxidative damage. These ROS-induced changes could enable sustained mitochondrial biogenesis during brown adipogenesis, and explain in part, the molecular basis for ROS hormesis.

molecular biology↗

bioRxiv2023

Assembly and analysis of the genome of Notholithocarpus densiflorus

Tanoak (Notholithocarpus densiflorus) is an evergreen tree in the Fagaceae family found in California and southern Oregon. Historically, tanoak acorns were an important food source for Native American tribes and the bark was used extensively in the leather tanning process. Long considered a disjunct relictual element of the Asian stone oaks (Lithocarpus spp.), phylogenetic analysis has determined that the tanoak is an example of convergent evolution. Tanoaks are deeply divergent from oaks (Quercus) of the Pacific Northwest and comprise a new genus with a single species. These trees are highly susceptible to sudden oak death (SOD), a plant pathogen (Phytophthora ramorum) that has caused widespread mortality of tanoaks. Here, we set out to assemble the genome and perform comparative studies among a number of individuals that demonstrated varying levels of susceptibility to SOD. First, we sequenced and de novo assembled a draft reference genome of N. densiflorus using co-barcoded library processing methods and an MGI DNBSEQ-G400 sequencer. To increase the contiguity of the final assembly, we also sequenced Oxford Nanopore (ONT) long reads to 30X coverage. To our knowledge, the draft genome reported here is one of the more contiguous and complete genomes of a tree species published until now, with a contig N50 of [~]1.2 Mb and a scaffold N50 of [~]2.1 Mb. In addition, we sequenced 11 genetically distinct individuals and mapped these onto the draft reference genome enabling the discovery of almost 25 million single nucleotide polymorphisms and [~]4.4 million small insertions and deletions. Finally, using co-barcoded data we were able to generate complete haplotype coverage of all 11 genomes.

genomics↗

bioRxiv2023

Defining the Cell Surface Cysteinome using Two-step Enrichment Proteomics

The plasma membrane proteome is a rich resource of functional and therapeutically relevant protein targets. Distinguished by high hydrophobicity, heavy glycosylation, disulfide-rich sequences, and low overall abundance, the cell surface proteome remains undersampled in established proteomic pipelines, including our own cysteine chemoproteomics platforms. Here we paired cell surface glycoprotein capture with cysteine chemoproteomics to establish a two-stage enrichment method that enables chemoproteomic profiling of cell Surface Cysteinome. Our "Cys-Surf" platform captures >2,800 total membrane protein cysteines in 1,046 proteins, including 1,907 residues not previously captured by bulk proteomic analysis. By pairing Cys-Surf with an isotopic chemoproteomic readout, we uncovered 821 total ligandable cysteines, including known and novel sites. Cys-Surf also robustly delineates redox-sensitive cysteines, including cysteines prone to activation-dependent changes to cysteine oxidation state and residues sensitive to addition of exogenous reductants. Exemplifying the capacity of Cys-Surf to delineate functionally important cysteines, we identified a redox sensitive cysteine in the low-density lipoprotein receptor (LDLR) that impacts both the protein localization and uptake of LDL particles. Taken together, the Cys-Surf platform, distinguished by its two-stage enrichment paradigm, represents a tailored approach to delineate the functional and therapeutic potential of the plasma membrane cysteinome.

biochemistry↗

bioRxiv2023

Ependymocytes control cerebrospinal fluid flow to the peripheral organs through periaxonal pathway

Mechanisms controlling movement of the CSF through the central canal towards the peripheral nerves are poorly characterized. We found that fluorescent dyes injected into cisterna magna are carried with cerebrospinal fluid (CSF) through the central canal and peripheral nerves to the peripheral organs such as liver, and pancreas. We also found close connection between spinal axons and ependymocytes, suggesting synaptic interactions. Serotonin, acting through the 5-HT2B receptors abundantly expressed in ependymal cells, trigger Ca2+ signal that induces polymerization of cytoskeleton protein F-actin, consequently reducing the volume of ependymocytes. Shrinkage of the latter opens one-way route to facilitate CSF outflow from the central canal into the spinal cord parenchyma and peripheral nerves. In liver, CSF is received by stellate cells. Ependymal control over transfer of the CSF from central canal to peripheral organs by the periaxonal space (PAS) represents a novel mechanism dynamically connecting the CNS with the periphery. In briefEpendymocytes control CSF flow from CNS to peripheral organs by periaxonal pathway, and serotonin evokes the ependymal shrinkage by the aggregation of F-actin. HighlightsEpendymocytes control CSF flow from central canal to peripheral organs; CSF flows through the peripheral periaxonal space to reach the peripheral organs; Serotonin makes ependymocytes shrunk by 5-HT2B receptor-mediated Ca2+ signaling and F-actin polymerization; The hepatic stellate cells are potential collectors of CSF in the liver.

neuroscience↗

bioRxiv2023

A consistent map in the medial entorhinal cortex supports spatial memory

The medial entorhinal cortex (MEC) is hypothesized to function as a cognitive map for memory-guided navigation. How this map develops during learning and influences memory remains unclear. By imaging MEC calcium dynamics while mice successfully learned a novel virtual environment over ten days, we discovered that the dynamics gradually became more spatially consistent and then stabilized. Additionally, grid cells in the MEC not only exhibited improved spatial tuning consistency, but also maintained stable phase relationships, suggesting a network mechanism involving synaptic plasticity and rigid recurrent connectivity to shape grid cell activity during learning. Increased c-Fos expression in the MEC in novel environments further supports the induction of synaptic plasticity. Unsuccessful learning lacked these activity features, indicating that a consistent map is specific for effective spatial memory. Finally, optogenetically disrupting spatial consistency of the map impaired memory-guided navigation in a well-learned environment. Thus, we demonstrate that the establishment of a spatially consistent MEC map across learning both correlates with, and is necessary for, successful spatial memory.

neuroscience↗

bioRxiv2023

GeneCompass: Deciphering Universal Gene Regulatory Mechanisms with Knowledge-Informed Cross-Species Foundation Model

Deciphering the universal gene regulatory mechanisms in diverse organisms holds great potential to advance our knowledge of fundamental life process and facilitate research on clinical applications. However, the traditional research paradigm primarily focuses on individual model organisms, resulting in limited collection and integration of complex features on various cell types across species. Recent breakthroughs in single-cell sequencing and advancements in deep learning techniques present an unprecedented opportunity to tackle this challenge. In this study, we developed GeneCompass, the first knowledge-informed, cross-species foundation model pre-trained on an extensive dataset of over 120 million single-cell transcriptomes from human and mouse. During pre-training, GeneCompass effectively integrates four types of biological prior knowledge to enhance the understanding of gene regulatory mechanisms in a self-supervised manner. Fine-tuning towards multiple downstream tasks, GeneCompass outperforms competing state-of-the-art models in multiple tasks on single species and unlocks new realms of cross-species biological investigation. Overall, GeneCompass marks a milestone in advancing knowledge of universal gene regulatory mechanisms and accelerating the discovery of key cell fate regulators and candidate targets for drug development.

bioinformatics↗

bioRxiv2023

Large-scale population genomics of Malayan pangolins reveals deep diversification and a new species

BackgroundArchipelagos and oceanic islands often present high percentage of endemism due to rapid speciation. The Malayan pangolin is a species distributing at both mainland (southern Yunnan, China) and oceanic islands via Malayan peninsula, which may result in deep differentiation among populations. In-depth investigation of population structure and genetic consequences for such species is of vital importance for their protection and conservation, practically for the critically endangered Malayan pangolin that is suffering from poaching, illegal trade, and habitat loss. ResultsHere we carried out a large-scale population genomic analysis for Malayan pangolins, and revealed three highly distinct genetic populations in this species, two of which are now being reported for the first time. Based on multiple lines of genomic and morphological evidence, we postulate the existence of a new pangolin species (Manis_1). Genetic diversity and recent inbreeding were both at a moderate level for both Malayan pangolins and Manis_1, but mainland Malayan pangolins presented relatively lower genetic diversity, higher inbreeding and fitness cost than island populations. ConclusionsWe found extremely deep and graded differentiation in Malayan pangolins, with two newly discovered genetic populations and a new pangolin species that is closely related to the Philippine pangolin than the typical Malayan pangolin, but a distant relative of the Indian pangolin. Anthropogenic factors did not significantly weaken the basis of genetic sustainability for Malayan pangolins, but mainland Malayan pangolins should be paid more attention for conservation due to higher genetic risks than island populations.

genomics↗

bioRxiv2023

Aster-dependent non-vesicular transport facilitates dietary cholesterol uptake

Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe (EZ), assists in the initial step of dietary cholesterol uptake. However, how cholesterol moves downstream of NPC1L1 is unknown. Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes, bridging NPC1L1 at the plasma membrane (PM) and ACAT2 in the endoplasmic reticulum (ER). Loss of NPC1L1 diminishes accessible PM cholesterol in enterocytes and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate cholesterol at the PM and display evidence of ER cholesterol depletion, including decreased cholesterol ester stores and activation of the SREBP-2 transcriptional pathway. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, we show that the Aster pathway can be targeted with a small molecule inhibitor to manipulate dietary cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption. One-Sentence SummaryIdentification of a targetable pathway for regulation of dietary cholesterol absorption

physiology↗

bioRxiv2023

YAP/TAZ enhance P-body formation to promote tumorigenesis

The role of Processing bodies (P-bodies) in tumorigenesis and tumor progression is not well understood. Here, we showed that the oncogenes YAP/TAZ promote P-body formation in a series of cancer cell lines. Mechanistically, both transcriptional activation of the P- body-related genes SAMD4A, AJUBA, and WTIP and transcriptional suppression of the tumor suppressor gene PNRC1 are involved in enhancing the effects of YAP/TAZ on P- body formation in CRC cells. By reexpression of PNRC1 or knockdown of P-body core genes (DDX6, DCP1A, and LSM14A), we determined that disruption of P-bodies attenuates cell proliferation, cell migration and tumor growth induced by overexpression of YAP5SA in CRC. Analysis of a pancancer CRISPR screen database (DepMap) revealed codependencies between YAP/TEAD and the P-body core genes and correlations between the mRNA levels of SAMD4A, AJUBA, WTIP, PNRC1 and YAP target genes. Our study suggests that the P-body is a new downstream effector of YAP/TAZ, which implies that reexpression of PNRC1 or disruption of P-bodies is a potential therapeutic strategy for tumors with active YAP.

cell biology↗

bioRxiv2023

Population genomics reveals extensive inbreeding and purging of mutational load in wild Amur tigers

The inbreeding is a big threat for the persistence of genetic diversity in small and isolated populations of endangered species. The homozygous genome could exacerbate inbreeding depression by introducing homozygous deleterious alleles in the population. However, purging of inbreeding loads as they become homozygotes in small populations could alleviate the depression. The Amur tiger (Panthera tigris altaica) is typically exists in small population living in forests in Northeast Asia and is among the most endangered animals on the planet with great symbolic significance of conservation. By comparing with captive individuals, we revealed substantially higher and more extensive inbreeding in the wild Amur tiger population (FROH=0.51) than in captive Amur tigers (FROH=0.26). We further found much less mutational loads in wild populations when compared with captive Amur tigers. However, the frequency of loss of function and deleterious nonsynonymous mutations inside ROH regions are much lower than that in non-ROH regions in both wild and captive Amur tigers, indicating the purging may had occurred in both populations but much effective in the wild population. In addition, we found the average frequency of deleterious alleles was much lower than that of neutral alleles in the wild population, indicating that the purifying selection contributed to the purging of mutational loads in the wild Amur tigers. These findings provide valuable genome-wide evidence to support the making of future conservation plans of wild Amur tigers.

genomics↗

bioRxiv2023

Genetic basis of expression and splicing underlying spike architecture in wheat (Triticum aestivum L.)

IntroductionWheat is one of the most important staple crops worldwide, and an important source of human protein and mineral element intake. Continuously increasing stable production of wheat is critical for global food security under the challenge of population growth and limited resource input. ObjectiveSpike architecture determines the potential grain yield of wheat. However, the mechanisms of transcriptional regulation of spike architecture in wheat remain largely unknown, limiting further genetic improvement of wheat yield. In this study we explored the genetic basis of spike architecture in wheat. MethodsPopulation RNA-seq methods were used to identify the eQTLs and sQTLs associated with spike architecture and applied this to dissection of the genetic basis of gene expression and splicing controlling these complex yield-related traits. ResultsIn total, 4,143 expression quantitative trait loci (eQTLs) and 12,933 splice QTLs (sQTLs) were identified in wheat based on 178 RNA-seq samples, revealing 774 cis-eQTLs and 321 cis-sQTLs for 86 eGenes and 73 sGenes, respectively. Integration of eQTLs and sQTLs with genome-wide association study (GWAS) identified dozens of additional novel candidate genes that may contribute to spike-related traits. Gene network analysis showed that eQTLs and sQTLs were widely involved in the co-expression modules that regulate wheat spike architecture. Notably, the eQTL locus AX-108754757 regulated the expression of 5 eGenes that negatively controled grain number per spike. AX-111592099 regulated both the splicing and expression of TraesCS7B02G442100, encoding an E3 ubiquitin ligase, and playing a central role in regulating spike length. ConclusionThis study provides new insights into the genetic basis of spike architecture. This improved understanding of spike-related traits in wheat will contribute to more rapid genetic improvement.

plant biology↗

bioRxiv2023

Four additional natural 7-deazaguanine derivatives in phages and how to make them

Bacteriophages and bacteria are engaged in a constant arms race, continually evolving new molecular tools to survive one another. To protect their genomic DNA from restriction enzymes, the most common bacterial defence systems, double-stranded DNA phages have evolved complex modifications that affect all four bases. This study focuses on modifications at position 7 of guanines. Eight derivatives of 7-deazaguanines were identified, including four previously unknown ones: 2-deoxy-7-(methylamino)methyl-7-deazaguanine (mdPreQ1), 2-deoxy-7-(formylamino)methyl-7-deazaguanine (fdPreQ1), 2-deoxy-7-deazaguanine (dDG), and 2-deoxy-7-carboxy-7-deazaguanine (dCDG). These modifications are inserted in DNA by a guanine transglycosylase named DpdA. Three subfamilies of DpdA had been previously characterized: bDpdA, DpdA1, and DpdA2. Two additional subfamilies were identified in this work: DpdA3, which allows for complete replacement of the guanines, and DpdA4, which is specific to archaeal viruses. Transglycosylases have now been identified in all phages and viruses carrying 7-deazaguanine modifications, indicating that the insertion of these modifications is a post-replication event. Three enzymes were predicted to be involved in the biosynthesis of these newly identified DNA modifications: 7-carboxy-7-deazaguanine decarboxylase (DpdL), dPreQ1 formyltransferase (DpdN), and dPreQ1 methyltransferase (DpdM), which was experimentally validated and harbors a unique fold not previously observed for nucleic acid methylases.

genomics↗

bioRxiv2023

Discovery and Engineering of the L-Threonine Aldolase from Neptunomonas Marine for Efficient Synthesis of β-Hydroxy-α-Amino Acids via C-C Formation

O_SCPLOWLC_SCPLOW-Threonine aldolases (LTAs) are attractive biocatalysts for synthesizing {beta}-hydroxy--amino acids (HAAs) via C-C bond formation in pharmaceuticals, although their industrial applications suffer from low activity and diastereoselectivity. Herein, we describe the discovery of a new LTA from Neptunomonas marine (NmLTA) that displays both ideal enzymatic activity (64.8 U/mg) and diastereoselectivity (89.5% diastereomeric excess; de) for the desired product O_SCPLOWLC_SCPLOW-threo-4-methylsulfonylphenylserine (O_SCPLOWLC_SCPLOW-threo-MPTS). Using X-ray crystallography, site-directed mutagenesis, and computational modeling, we propose a "dual-conformation" mechanism for the diastereoselectivity control of NmLTA, whereby the incoming 4-methylsulfonylbenzaldehyde (4-MTB) could potentially bind at the NmLTA active site in two distinct orientations, potentially forming two diastereoisomers (threo- or erythro-form products). Importantly, two key NmLTA residues H140 and Y319 play critical roles in fine-tuning the binding mode of 4-MTB, supported by our site-mutagenesis assays. Uncovering of the catalytic mechanism in NmLTA guides us to further improve the diastereoselectivity of this enzyme. A triple variant of NmLTA (N18S/Q39R/Y319L; SRL) exhibited both improved diastereoselectivity (de value > 99%) and enzymatic activity (95.7 U/mg) for the synthesis of O_SCPLOWLC_SCPLOW-threo-MPTS compared with that of wild type. The preparative gram-scale synthesis for O_SCPLOWLC_SCPLOW-threo-MPTS with the SRL variant produced a space-time yield of up to 9.0 g L-1h-1, suggesting a potential role as a robust C-C bond synthetic tool for industrial synthesis of HAAs at a preparative scale. Finally, the SRL variant accepted a wider range of aromatic aldehyde derivatives as substrates and exhibited improved diastereoselectivity toward para-site substituents. This work provides deep structural insights into the molecular mechanism underlying the catalysis in NmLTA and pinpoints the key structural motifs responsible for regulating the diastereoselectivity control, thereby guiding future attempts for protein engineering of various LTAs from different sources.

biochemistry↗

bioRxiv2023

Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing

BackgroundDominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena played a major role in quantitative genetics. However, today most genome-wide association studies (GWAS) assume alleles act additively. MethodsWe systematically investigated both dominance - here representing any non-additive effect - and additivity across 574 physiological and gene expression traits in three mammalian models: a Pig F2 Intercross, a Rat Heterogeneous Stock and a Mouse Heterogeneous Stock. ResultsIn all species, and across all physiological traits, dominance accounts for about one quarter of the heritable variance. Hematological and immunological traits exhibit the highest dominance variance, possibly reflecting balancing selection in response to pathogens. Although most quantitative trait loci (QTLs) are detectable assuming additivity, we identified 154, 64 and 62 novel dominance QTLs in pigs, rats and mice respectively, that were undetectable as additive QTLs. Similarly, even though most cis-acting eQTLs are additive, we observed a large fraction of dominance variance in gene expression, and trans-acting eQTLs are enriched for dominance. Genes causal for dominance physiological QTLs are less likely to be physically linked to their QTLs but instead act via trans-acting dominance eQTLs. In addition, in HS rat transcriptomes, thousands of eQTLs associate with alternate transcripts and exhibit complex additive and dominant architectures, suggesting a mechanism for dominance. ConclusionsAlthough heritability is predominantly additive, many mammalian genetic effects are dominant and likely arise through distinct mechanisms. It is therefore advantageous to consider both additive and dominance effects in GWAS to improve power and uncover causality.

genetics↗

bioRxiv2023

Viruses encode tRNA and anti-retron to evade bacterial immunity

Retrons are bacterial genetic retroelements that encode reverse transcriptase capable of producing multicopy single-stranded DNA (msDNA) and function as antiphage defense systems. Phages employ several strategies to counter the host defense systems, but no mechanisms for evading retrons are known. Here, we show that tRNATyr and Rad (retron anti-defense) of T5 phage family inhibit the defense activity of retron 78 and a broad range of retrons, respectively. The effector protein of retron 78, ptuAB, specifically degraded tRNATyr leading abortive infection, but phage countervailed this defense by supplying tRNATyr. Rad inhibited retron function by degrading noncoding RNA, the precursor of msDNA. In summary, we demonstrated that viruses encode at least two independent strategies for overcoming bacterial defense systems: anti-defense, such as Rad, and defense canceler, like tRNA.

microbiology↗

bioRxiv2023

Scalable Solar-Driven Chemical Production by Semiconductor Biohybrids Synthesized from Wastewater Pollutants

Semiconductors biohybrids integrate the best of biological catalysts and semiconductor nanomaterials for solar-to-chemical conversion. To realize the potential of hybrid systems at the commercial level, it remains an urgent need for cost-competitive and environmentally friendly approaches to scaling up. Here, we successfully tackle this challenge through developing biohybrid route that co-utilize multi-pollutants in wastewater to produce semiconductor biohybrids in-situ for solar-to-chemical production. To achieve cost-effective biohybrid production, we introduced an aerobic sulfate reduction pathway into Vibrio natriegens to enable the direct utilization of the heavy metal ions (i.e., Cd2+), sulfate, and organics in the wastewater to biosynthesize functional semiconductor nanoparticles in living V. natriegens. Furthermore, 2,3-butanediol biosynthetic pathway was introduced into the V. natriegens hybrid to couple the solar energy for enhanced bioproduction. We demonstrated the scalability of this system in a 5-L illuminated fermenter using wastewater as the feedstock, which resulted in production of 13 g/L of 2,3-butanediol. Life cycle analysis showed this specific biohybrid route had a significantly lower cost and reduced CO2 emission compared to both pure sugars fermentation and fossil-based routes. In addition to providing a promising step toward sustainable commercializing semiconductor biohybrids for biomanufacturing, our work may lead to hybrid living matter toward future waste to wealth conversion.

synthetic biology↗

bioRxiv2023

Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses

Plasmodium falciparum causes the most severe malaria and is exposed to various environmental and physiological stresses in the human host. Given that GCN5 plays a critical role in regulating stress responses in model organisms, we aimed to elucidate PfGCN5s function in stress responses in P. falciparum. The protein level of PfGCN5 was substantially induced under three stress conditions (heat shock, low glucose starvation, and dihydroartemisinin, the active metabolite of artemisinin (ART)). With a TetR-DOZI conditional knockdown (KD) system, we successfully down-regulated PfGCN5 to [~]50% and found that KD parasites became more sensitive to all three stress conditions. Transcriptomic analysis via RNA-seq identified [~]1,000 up-and down-regulated genes in the wildtype (WT) and KD parasites under these stress conditions. Importantly, DHA induced transcriptional alteration of many genes involved in many aspects of stress responses, which were heavily shared among the altered genes under heat shock and low glucose conditions, including ART-resistance-related genes such as K13 and coronin. Based on the expression pattern between WT and KD parasites under three stress conditions, [~]300-400 genes were identified to be involved in PfGCN5-dependent, general and stress-condition-specific responses with high levels of overlaps among three stress conditions. Notably, using ring-stage survival assay (RSA), we found that KD or inhibition of PfGCN5 could sensitize the ART-resistant parasites to the DHA treatment. All these indicate that PfGCN5 is pivotal in regulating general and ART-resistance-related stress responses in malaria parasites, implicating PfGCN5 as a potential target for malaria intervention. IMPORTANCEMalaria leads to about half a million deaths annually and these casualties were majorly caused by the infection of Plasmodium falciparum. This parasite strives to survive by defending against a variety of stress conditions, such as malaria cyclical fever (heat shock), starvation due to low blood sugar (glucose) levels (hypoglycemia), and drug treatment. Previous studies have revealed that P. falciparum has developed unique stress responses to different stresses including ART treatment, and ART-resistant parasites harbor elevated stress responses. In this study, we provide critical evidence on the role of PfGCN5, a histone modifier, and a chromatin coactivator, in regulating general and stress-specific responses in malaria parasites, indicating that PfGCN5 can be used as a potential target for anti-malaria intervention.

microbiology↗

bioRxiv2022

MalariaSED: a deep learning framework to decipher the regulatory contributions of noncoding variants in malaria parasites

Malaria remains one of the deadliest infectious diseases. Transcriptional regulation effects of noncoding variants in this unusual genome of malaria parasites remain elusive. We developed a sequence-based, ab initio deep learning framework, MalariaSED, for predicting chromatin profiles in malaria parasites. The MalariaSED performance was validated by published ChIP-qPCR and TF motifs results. Applying MalariaSED to [~]1.3 million variants shows that geographically differentiated noncoding variants are associated with parasite invasion and drug resistance. Further analysis reveals chromatin accessibility changes at Plasmodium falciparum rings are partly associated with artemisinin resistance. MalariaSED illuminates the potential functional roles of noncoding variants in malaria parasites.

bioinformatics↗