Biology subjects

Islam, M. R.

Publications and source records attributed to Islam, M. R..

35 records · Page 2Linked to original sources

bioRxiv2022

Comparative Phylogenetic Analysis and Transcriptomic Profiling of Dengue (DENV-3 genotype I) Outbreak in 2021 in Bangladesh

ObjectivesThe lack of a dengue disease animal model and the complex immune interaction in dengue infection hinders the study of host response and immunopathogenesis. The development of next-generation sequencing (NGS) technology allowed the researchers to study the transcriptomic profiles of human in-depth. We, therefore, implicated phylodynamic and transcriptomic approaches through NGS technology to know the origin of dengue virus (DENV) and their host response in infected patients with dengue fever. MethodsTo determine the whole genome sequences of the dengue virus and their transcriptomic profiles, RNA was extracted from the serum samples of 3 healthy, and 21 dengue patients. These samples were custom performed at phylogenetic, phylodynamic, differential express gene (DEG), and gene ontology (GO) using respective bioinformatics tools. ResultsThe whole genome sequence analysis revealed that the total number of nucleotide ranges on these serum RNA samples were in between 10647 and 10707. Phylogenetic tree analysis showed that these strains were belonged to DENV-3 genotype I. Phylodynamic analysis showed that the 2021 epidemic isolates were clade shifted and maintained as a new clade in compared to 2019 epidemic. Transcriptome analysis mapped a total of 19267 expressed genes. Of them, there were higher expression of genes in dengue-positive samples (n = 17375) with a count of 6953 unique genes in comparison to healthy controls (n = 12314) with a count of 1892 unique genes. A total of 2686 DEGs were identified in a host factor-independent manner in dengue patients with a q-value < 0.05. DESeq2 plot counts function of the top 24 genes with the smallest q-values of differential gene expression of RNA-seq data showed that 11 genes were upregulated, whereas 13 genes were downregulated. GO analysis showed a significant upregulation (p = <0.001) in a process of multicellular organismal, nervous system, sensory perception of chemical stimulus, and G protein-coupled receptor signalling pathways in the dengue patients. However, there were a significant downregulation (p = < 0.001) of intracellular component, cellular anatomical entity, and protein-containing complex in dengue patients. Most importantly, there was significant increase of a classes of immunity protein (Cytokines especially TGF-{beta}1, chemokines, inflammasome, and factors for blood coagulations) in dengue patients in compared to the healthy controls, with increased GO of immune system process. In addition, upregulation of toll receptor (TLR) signalling pathways were also initiated in the patients infected with dengue virus. These TLR pathways were particularly involved for the activation of innate in couple with adaptive immune system that probably involved the rapid elimination of dengue virus infected cells. These differentially expressed genes could be further investigated for target based prophylactic interventions for dengue. ConclusionThis is a first report to document the complete genomic features of dengue, and differentially expressed genes in patients with dengue virus in Bangladesh. These genes may have diagnostic and therapeutic values for dengue infection. Continual genomic surveillance is required to further investigate the shift in dominant genotypes in relation to viral pathogenesis.

evolutionary biology↗

bioRxiv2021

Sensing Local Field Potentials with a Directional and Scalable Depth Array: DISC

A variety of electrophysiology tools are available to the neurosurgeon for diagnosis, functional therapy, and neural prosthetics. However, no tool can currently address these three critical needs: (i) access to all cortical regions in a minimally invasive manner; (ii) recordings with microscale, mesoscale, and macroscale resolutions simultaneously; and (iii) access to spatially distant multiple brain regions that constitute distributed cognitive networks. We present a novel device for recording local field potentials (LFPs) with the form factor of a stereo-electroencephalographic electrode but combined with radially positioned microelectrodes and using the lead body to shield LFP sources, enabling directional sensitivity and scalability, referred to as the DISC array. As predicted by our electro-quasistatic models, DISC demonstrated significantly improved signal-to-noise ratio, directional sensitivity, and decoding accuracy from rat barrel cortex recordings during whisker stimulation. Critically, DISC demonstrated equivalent fidelity to conventional electrodes at the macroscale and uniquely, revealed stereoscopic information about current source density. Directional sensitivity of LFPs may significantly improve brain-computer interfaces and many diagnostic procedures, including epilepsy foci detection and deep brain targeting.

bioengineering↗

bioRxiv2021

Stomatal responses at different vegetative stages of selected maize varieties of Bangladesh under water deficit condition

Drought stress causes stomatal behavior change in most plants. Water deficit condition caused by drought is one of the most significant abiotic factors reducing plant growth, development, reproductive efficiency, and photosynthesis, resulting in yield loss. Maize (Zea mays L.) holds a superior position among all the cereals due to its versatile use in the food, feed, and alcohol industries. A common demonstrative feature of a complex network of signaling pathways led by predominantly abscisic acid under drought conditions is stomatal aperture reduction or stomatal closure, which allows the plant to reduce water loss through the stomatal pore and to sustain a long time on water deficit condition. This study analyses the stomatal density, stomatal closure percentages, and guard cell aperture reduction using a microscopy-based rapid & simple method to compare guard cell response & morphological variations of three hybrid maize varieties viz. BHM (BARI hybrid maize)-7, BHM-9, and BHM-13 developed by Bangladesh Agricultural Research Institute (BARI). A drought treatment was applied to all varieties at two different vegetative stages, vegetative stage 3 (V3) and V5, until they reach V4 and V6, respectively. After drought exposure at the V4 stage, the percentage of closed stomata of BHM-7, BHM-9, and BHM-13 was 21%, 23%, and 33%, respectively. The reduction in the guard cell aperture ratio of BHM-7, BHM-9, and BHM-13 was 14.83%, 10.92%, and 33.85%, respectively. At the V6 stage, for the second set of plants, the closed stomata of BHM-7, BHM-9, and BHM-13 were 18%, 21%, and 34%, respectively. The rate of reduction in guard cell aperture ratio of BHM-7, BHM-9, and BHM-13 was 5.52%, 2.48%, and 38.75%, respectively. Therefore, BHM-13 showed maximum drought adaptation capacity compared to BHM-7 and BHM-9 due to the highest percentage of closed stomata and the highest percentage of reduction in aperture ratio.

plant biology↗

bioRxiv2021

Postnatal SETD1B is essential for learning and the regulation of neuronal plasticity genes

Histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to syndromic intellectual disability but its role in the postnatal brain has not been studied yet. Here we employ mice that lack Setd1b from excitatory neurons of the postnatal forebrain and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that SETD1B controls the expression of genes with a broad H3K4me3 peak at their promoters that represent neuronal enriched genes linked to learning and memory function. Comparative analysis to corresponding data from conditional Kmt2a and Kmt2b knockout mice suggests that this function is specific to SETD1B. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-mediated regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

neuroscience↗

bioRxiv2021

Microbiome dysbiosis regulates the level of energy production under anaerobic condition

The microbiome of the anaerobic digester (AD) regulates the level of energy production. To assess the microbiome dysbiosis in different stages of anaerobic digestion, we analyzed 16 samples dividing into four groups (Group-I = 2; Group-II = 5; Group-III = 5 and Group-IV = 4) through whole metagenome sequencing (WMS). The physicochemical analysis revealed that highest CH4 production (74.1%, on Day 35 of digestion) was associated with decreased amount of non-metal (phosphorus and sulfur) and heavy metals (chromium, lead and nickel). The WMS generated 380.04 million reads mapped to ~ 2800 distinct bacterial, archaeal and viral genomes through PathoScope (PS) and MG-RAST (MR) analyses. The PS analysis detected 768, 1421, 1819 and 1774 bacterial strains in Group-I, Group-II, Group-III and Group-IV, respectively which were represented by Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Spirochaetes and Fibrobacteres (> 93.0% of the total abundances). The archaeal fraction of the AD microbiomes was represented by 343 strains, of which 95.90% strains shared across these metagenomes. The indicator species analysis showed that Methanosarcina vacuolate, Dehalococcoides mccartyi, Methanosarcina sp. Kolksee and Methanosarcina barkeri were the highly specific for energy production in Group-III and Group-IV. However, most of the indicator phylotypes displayed reduced abundance in the initial stage of biogas production (Group-I and Group-II) compared to their increased relative abundances in Group-IV (Day 35). The correlation network analysis showed that different strains of Euryarcheota and Firmicutes phyla were associated with highest level (74.1%) of energy production (Group-IV). In addition to taxonomic dysbiosis, top CH4 producing microbiomes showed increased genomic functional activities related to one carbon and biotin metabolism, oxidative stress, proteolytic pathways, MT1-MMP pericellular network, acetyl-CoA production, motility and chemotaxis. This study reveals distinct changes in composition and diversity of the AD microbiomes including different indicator species, and their genomic features that are highly specific for energy production.

microbiology↗

bioRxiv2020

CYP2C192, CYP2C1917 and ITGB3 (PlA1/A2) polymorphisms and resulting therapeutic alterations of clopidogrel and aspirin: A clinical screening among CVD patients who undergone PCI

IntroductionClopidogrel and aspirin are at the base of treatment in conditions like arterial thrombosis and after patients have undergone percutaneous coronary intervention. But frequently found CYP2C19*2 and CYP2C19*17 polymorphisms and some variants of the ITGB3 gene cause alteration in the therapeutic effectiveness of this drug. MethodsOne thousand cardiovascular patients were recruited for each drug under study. Their blood was collected to analyze the genotype using PCR-RFLP and T-ARMS-PCR method for clopidogrel and aspirin respectively. The PCR products for clopidogrel were screened with agarose gel electrophoresis and then digested with SmaIfor CYP2C19*2 and Nsil-HF for CYP2C19*17. The digested products of clopidogrel and the ARMS-PCR product of aspirin were run on 2% AGE to analyze the polymorphisms. ResultsIn our outcome, the percentage of hetero and mutant homozygous people in CYP2C19*2 polymorphism (loss-of-function allele) was 64.1% and for CYP2C19*17 (gain-of-function allele) was 22.3%. For ITGB3 polymorphism, it was found that 84.1% of them belonged to the homozygous group while 15.6% was heterozygous and only 0.3% were mutant homozygous patients. ConclusionOur study findings were quite compatible with the results of some other studies in other ethnic groups. This phenomenon suggested for modification of dose or application of alternative generics in patients who are under the risk of therapeutic failure or toxicity produced by these drugs.

genetics↗

bioRxiv2020

Evolutionary dynamics of SARS-CoV-2 nucleocapsid protein (N protein) and its consequences

The emerging novel coronavirus SARS-CoV-2 has created a global confusing pandemic health crisis that warrants an accurate and detailed characterization of the rapidly evolving viral genome for understanding its epidemiology, pathogenesis and containment. We explored 61,485 sequences of the Nucleocapsid (N) protein, a potent diagnostic and prophylactic target, for identifying the mutations to review their roles in RT-PCR based diagnosis and observe consequent impacts. Compared to the Wuhan reference strain, a total of 1034 unique nucleotide mutations were identified in the mutant strains (49.15%, n=30,221) globally. Of these mutations, 367 occupy primer binding sites including 3-end mismatch to primer-pair of 11 well characterized primer sets. Noteworthy, CDC (USA) recommended N2 primer set contained lower mismatch than the other primer sets. Moreover, 684 amino acid (aa) substitutions located across 317 (75.66% of total aa) unique positions including 82, 21, and 83 of those in RNA binding N-terminal domain (NTD), SR-rich region, and C-terminal dimerization domain (CTD), respectively. Moreover, 11 in-frame deletions were revealed, mostly (n =10) within the highly flexible linker region, and the rest within the NTD region. Furthermore, we predicted the possible consequences of high-frequency mutations ([≥] 20) and deletions on the tertiary structure of the N protein. Remarkably, we observed that high frequency (67.94% of mutated sequences) coevolving mutations (R203K and G204R) destabilized and decreased overall structural flexibility. Despite being proposed as the alternate target to spike protein for vaccine and therapeutics, ongoing nonsynonymous evolution of the N protein may challenge the endeavors, thus need further immunoinformatics analyses. Therefore, continuous monitoring is required for tracing the ongoing evolution of the SARS-CoV-2 N protein in prophylactic and diagnostic interventions.

evolutionary biology↗

bioRxiv2020

Microbiome Dynamics of Bovine Mastitis Progression and Genomic Determinants

The milk of lactating cows presents a complex ecosystem of interconnected microbial communities which can impose a significant influence on the pathophysiology of mastitis. Previously, we reported the alteration of microbiome (bacteria, archaea, virus) composition between clinical mastitis (CM) and healthy (H) milk. We hypothesized possible dynamic shifts of microbiome compositions with the progress of different pathological states of mastitis (CM, Recurrent CM; RCM, Subclinical Mastitis; SCM) determined by its favoring genomic potentials. To evaluate this hypothesis, we employed whole metagenome sequencing (WMS) in 20 milk samples (CM = 5, RCM = 6, SCM = 4, H = 5) to unravel the microbiome dynamics, interrelation, and relevant metabolic functions. PathoScope (PS) and MG-RAST (MR) analyses mapped the WMS data to 442 bacterial, 58 archaeal and 48 viral genomes with distinct variation in microbiome composition and abundances across these metagenomes (CM>H>RCM>SCM). PS analysis identified 385, 65, 80 and 144 bacterial strains in CM, RCM, SCM, and H milk, respectively, with an inclusion of 67.19% previously unreported opportunistic strains in mastitis metagenomes. Moreover, MR detected 56, 13, 9 and 46 archaeal, and 40, 24, 11 and 37 viral genera in CM, RCM, SCM and H-milk metagenomes, respectively. The CM-microbiomes had closest association with RCM-microbiomes followed by SCM, and H-microbiomes. Furthermore, we identified 333, 304, 183 and 50 virulence factors-associated genes (VFGs), and 48, 31, 11 and 6 antibiotic resistance genes (AGRs) in CM, RCM, SCM, and H-microbiomes, respectively, showing a significant correlation between the relative abundances of VFGs (p = 0.001), ARGs (p = 0.0001), and associated bacterial taxa. We also detected correlated variations in the presence and abundance of several metabolic functional genes related to bacterial colonization, proliferation, chemotaxis, motility and invasion, oxidative stress, virulence and pathogenicity, phage integration and excision, biofilm-formation, and quorum-sensing to be associated with different episodes of mastitis. Therefore, profiling the dynamics of microbiome in different states of mastitis, concurrent VFGs, ARGs, and genomic functional correlations will contribute to developing microbiome-based diagnostics and therapeutics for bovine mastitis, and carries significant implications on curtailing the economic fallout from this disease.

microbiology↗

bioRxiv2020

Comprehensive annotations of the mutational spectra of SARS-CoV-2 spike protein: a fast and accurate pipeline

In order to explore nonsynonymous mutations and deletions in the spike (S) protein of SARS-CoV-2, we comprehensively analyzed 35,750 complete S protein gene sequences from across six continents and five climate zones around the world, as documented in the GISAID database as of June 24th, 2020. Through a custom Python-based pipeline for analyzing mutations, we identified 27,801 (77.77 % of spike sequences) mutated strains compared to Wuhan-Hu-1 strain. 84.40% of these strains had only single amino-acid (aa) substitution mutations, but an outlier strain from Bosnia and Herzegovina (EPI_ISL_463893) was found to possess six aa substitutions. The D614G variant of the major G clade was found to be predominant across circulating strains in all climates. We also identified 988 unique aa substitution mutations distributed across 660 positions within the spike protein, with eleven sites showing high variability - these sites had four types of aa variations at each position. Besides, 17 in-frame deletions at four major regions (three in N-terminal domain and one just downstream of the RBD) may have possible impact on attenuation. Moreover, the mutational frequency differed significantly (p= 0.003, Kruskal-Wallis test) among the SARS-CoV-2 strains worldwide. This study presents a fast and accurate pipeline for identifying nonsynonymous mutations and deletions from large dataset for any particular protein coding sequence and presents this S protein data as representative analysis. By using separate multi-sequence alignment with MAFFT, removing ambiguous sequences and in-frame stop codons, and utilizing pairwise alignment, this method can derive nonsynonymus mutations (Reference:Position:Strain). We believe this will aid in the surveillance of any proteins encoded by SARS-CoV-2, and will prove to be crucial in tracking the ever-increasing variation of many other divergent RNA viruses in the future.

evolutionary biology↗

bioRxiv2020

ProtTox: Toxin identification from Protein Sequences

Toxin classification of protein sequences is a challenging task with real world applications in healthcare and synthetic biology. Due to an ever expanding database of proteins and the inordinate cost of manual annotation, automated machine learning based approaches are crucial. Approaches need to overcome challenges of homology, multi-functionality, and structural diversity among proteins in this task. We propose a novel deep learning based method ProtTox, that aims to address some of the shortcomings of previous approaches in classifying proteins as toxins or not. Our method achieves a performance of 0.812 F1-score which is about 5% higher than the closest performing baseline.

bioinformatics↗

bioRxiv2020

Evaluation of Neuropharmacological Effects of Different Chemical Extracts of Flemingia Stricta (Roxb.) Leaves.

BackgroundTraditional preparation of the leaf of Flemingia stricta (Fabaceae) Roxb., a medicinal plant of the Indian subcontinent, has been used for treatment of different diseases as herbal preparation. Our purpose was to analyze Neuropharmacological effects of different chemical extracts of Flemingia stricta Roxb. as particular form of behavioral inhibition that occurs in response to novel environmental events. MethodsIn present study, the anxiogenic activity of crude extracts of Flemingia stricta leaves was determined using standard animal behavioral models, such as hole cross and open field; Sedative property and anxiolytic potential were assessed by conducting thiopental sodium induced sleeping times tests and elevated plus maze test respectively. ResultsThe crude extracts at both dose (200 and 400mg/kg) exhibited a significant (P<0.05, P<0.01) dose-dependent suppression of motor activity and exploratory activity of mice in both open field and hole cross test. In anxiolytic study, extracts displayed increased percentage of entry into open arm at the dose of 200 and 400mg/kg. Extracts produced a significant (P<0.05, P<0.01) increase in sleeping duration and reduction of onset of sleep compared to sodium thiopental at both doses (200 and 400mg/kg). ConclusionThis study demonstrates that the treated extracts have significant central nervous system depressant effect. Further studies on the active constituent of the extract can provide approaches for therapeutic intervention.

pharmacology and toxicology↗

bioRxiv2020

Epitope-based chimeric peptide vaccine design against S, M and E proteins of SARS-CoV-2 etiologic agent of global pandemic COVID-19: an in silico approach

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19), a public health emergency of international concern declared by the World Health Organization (WHO). An immuno-informatics approach along with comparative genomic was applied to design a multi-epitope-based peptide vaccine against SARS-CoV-2 combining the antigenic epitopes of the S, M and E proteins. The tertiary structure was predicted, refined and validated using advanced bioinformatics tools. The candidate vaccine showed an average of [≥] 90.0% world population coverage for different ethnic groups. Molecular docking of the chimeric vaccine peptide with the immune receptors (TLR3 and TLR4) predicted efficient binding. Immune simulation predicted significant primary immune response with increased IgM and secondary immune response with high levels of both IgG1 and IgG2. It also increased the proliferation of T-helper cells and cytotoxic T-cells along with the increased INF-{gamma} and IL-2 cytokines. The codon optimization and mRNA secondary structure prediction revealed the chimera is suitable for high-level expression and cloning. Overall, the constructed recombinant chimeric vaccine candidate demonstrated significant potential and can be considered for clinical validation to fight against this global threat, COVID-19.

microbiology↗

bioRxiv2020

Epigenetic gene-expression links heart failure to memory impairment

In current clinical practice care of diseased patients is often restricted to separated disciplines. However, such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age-associated dementias. The underlying molecular mechanisms are presently unknown and thus corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms we show that heart failure leads to specific changes in hippocampal gene-expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.

neuroscience↗

bioRxiv2019

Assessment of Water Stress Tolerance in Mungbean Induced by Polyethyline Glycol

Water scarcity is a common hindrance of crop production in the globe especially in dry regions due to low precipitation along with high air temperature. Mungbean is a valuable pulse crop faced considerable amount of water shortage during its growing periods (March-May). Thus, the study was carried out to find out the variability and diversity present in the mungbean genotypes based on genetic variation of germination and seedling growth traits induced by polyethyline glycol (PEG-6000) stress (-0.7, -1, -2 and -4 bar). Seeds of each genotype was placed in a 9 cm diameter petridish containing sand bed that moistened by respective prepared PEG solutions and allowed to grow up to 10 days after placement. The result showed that the phenotypic coefficient of variation was significantly greater than the genotypic coefficient of variation for the entire studies traits, representing that these traits was influence by the environmental factors. The heritability showed moderate to high (24.26%-99.19%) under the observed traits indicating that these traits were under the control of additive genetic effects. The clustering pattern exhibited that cluster III were the largest ones with eleven genotypes. In case of contribution of different traits, the first five components were found to contribute for 98.19 % of the total variation while only first two components contributed for 82.12 % variation. The greater inter-cluster distance was found among the cluster I with II, III, IV and V. The maximum intra-cluster distance was observed in the cluster II (0.12). The genotypes in the cluster V recorded for greater performance by giving the highest mean value for germination, coefficient of germination, speed of germination, vigor index, shoot length and root length. This mean that genotype under cluster V have any gene or mechanism which responsible for tolerant higher level of water stress. The results of the study can be caring for establishing assortment criteria for water stress tolerant mungbean genotypes under breeding program.

plant biology↗

bioRxiv2019

Evaluation of the impact of Shigella virulence genes on the basis of clinical features observed in patients with shigellosis

Shigella is still attributable to nearly 164,300 deaths annually, mostly in sub-Saharan Africa and South Asian young children, remaining as a major public health threat, especially in the developing countries. Our goal was to study the association between Shigella virulence genes and clinical features observed in shigellosis. Therefore, 61 S. flexneri strains were investigated, isolated from patients from a tertiary level facility in Bangladesh between 2009 to 2013. Subsequently, the presence of 140 MDa large virulence plasmid (p140), virulence (ipaH, ial), toxin (set, sen) and T3SS related genes (virB, ipaBCD, ipgC, ipgB1, ipgA, icsB, ipgD, ipgE, ipgF, mxiH, mxiI, mxiK, mxiE, mxiC, spa15, spa47, spa32 and spa24) were evaluated. p140 was found in 79% (n=48) cases. ipaBCD was found in 90% (n=55) strains, while seven of them were missing p140. However, ial was found in 89% isolates, and ipgC and ipgE in 85% cases. The prevalence of the rest of the genes was less than 85%. These findings were then compared against the clinical features of each of the corresponding pathogens, and several statistically significant correlations were observed (all p<0.05). Briefly, the enterotoxin genes (set, sen) and another virulence gene (ial) were found significantly associated with several clinical features of shigellosis, including bloody mucoid stool, rectal straining, fever, and abdominal pain. Our findings reiterate that the diarrheal disease severity is significantly associated with the enterotoxin producing Shigella infection, also suggesting that the T3SS related virulence genes might be translocated elsewhere other than the 140 MDa large virulence plasmid.

microbiology↗

bioRxiv2019

Atypical Protein Kinase C iota (PKC{lambda}/{iota}) Ensures Mammalian Development by Establishing the Maternal-Fetal Exchange Interface

In utero mammalian development relies on the establishment of the maternal-fetal exchange interface, which ensures transportation of nutrients and gases between the mother and the fetus. This exchange interface is established via development of multinucleated syncytiotrophoblast cells (SynTs) during placentation. In mouse, SynTs develop via differentiation of the trophoblast progenitor cells (TSPCs) of the placenta primordium and in human, SynTs are developed via differentiation of villous cytotrophoblast (CTB) progenitors. Despite the critical need in pregnancy progression, conserved signaling mechanisms that ensure SynT development are poorly understood. Herein, we show that Atypical Protein Kinase C iota (PKC{lambda}/I) plays an essential role in establishing the SynT differentiation program in trophoblast progenitors. Loss of PKC{lambda}/I in the mouse TSPCs abrogates SynT development leading to embryonic death at ~E9.0. We also show that PKC{lambda}/I-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. PKC{lambda}/I is selectively expressed in the first-trimester CTBs of a developing human placenta. Furthermore, loss of PKC{lambda}/I in CTB-derived human trophoblast stem cells (Human TSCs) impairs their SynT differentiation potential both in vitro and after transplantation in immunocompromised mice. Our mechanistic analyses indicate that PKC{lambda}/I signaling maintains expression of GCM1, GATA2, and PPAR{gamma}, which are key transcription factors to instigate SynT differentiation programs in both mouse and human trophoblast progenitors. Our study uncovers a conserved molecular mechanism, in which PKC{lambda}/I signaling regulates establishment of the maternal-fetal exchange surface by promoting trophoblast progenitor to SynT transition during placentation.

developmental biology↗

bioRxiv2019

Trophoblast paracrine signaling regulates placental hematoendothelial niche

The placenta acts as a major organ for hematopoiesis. It is believed that placental hematopoietic stem and progenitor cells (HSPCs) migrate to the fetal liver to ensure optimum hematopoiesis in the developing embryo. The labyrinth vasculature in a mid-gestation mouse placenta provides a niche for the definitive hematopoietic stem cell (HSC) generation and expansion. It has been proposed that these processes are regulated by a host of paracrine factors secreted by trophoblast giant cells (TGCs) at the maternal-fetal interface. However, the molecular mechanism by which the TGCs regulate the hematoendothelial niche in a developing placenta is yet to be defined. Using a TGC-specific Gata2 and Gata3 double knockout mouse model, we show that the loss of GATA2 and GATA3 at the TGC layer leads to fetal growth retardation and embryonic death due to disruptions in the delicate hematopoietic-angiogenic balance in the developing placenta. Using single-cell RNA-Seq analyses, we also show that the loss of GATA factors in the TGCs results in the loss of HSC population within the placental labyrinth and is associated with defective placental angiogenesis. Interestingly, we also found that this TGC-specific GATA factor-loss leads to impaired differentiation and distribution of trophoblast progenitor cells. Our study helps to define the GATA-dependent non-autonomous signaling mechanisms of the primary parietal trophoblast giant cells by which it regulates the delicate hematopoietic-angiogenic balance in the developing placenta.

developmental biology↗