Identification of a molecular network regulated by multiple ASD high risk genes.

Genetic sequencing has identified high-confidence ASD risk genes with loss-of-function mutations. How the haploinsufficiency of distinct ASD risk genes causes ASD remains to be elucidated. In this study, we examined the role of four top-ranking ASD risk genes, ADNP, KDM6B, CHD2, and MED13, in gene expression regulation. ChIP-seq analysis reveals that gene targets with the binding of these ASD risk genes at promoters are enriched in RNA processing and DNA repair. Many of these targets are found in ASD gene database (SFARI), and are involved in transcription regulation and chromatin remodeling. Common gene targets of these ASD risk genes include a network of high confidence ASD genes associated with gene expression regulation, such as CTNNB1 and SMARCA4. We further directly examined the transcriptional impact of the deficiency of these ASD risk genes. Our mRNA profiling with qPCR assays in cells with the knockdown of Adnp, Kdm6b, Chd2 or Med13 has revealed an intricate pattern of their cross-regulation, as well as their influence on the expression of other ASD genes. In addition, some synaptic genes, such as Snap25 and Nrxn1, are strongly regulated by deficiency of the four ASD risk genes, which could be through the direct binding at promoters or indirectly through the targets like Ctnnb1 or Smarca4. The identification of convergent and divergent gene targets that are regulated by multiple ASD risk genes will help to understand the molecular mechanisms underlying common and unique phenotypes associated with haploinsufficiency of ASD-associated genes.

Unveiling the Cell Wall-Targeting Mechanisms and Multifaceted Virulence Modulation by a Eugenol Glycoconjugate against Aspergillus fumigatus: Insights from in vitro and in ovo Studies.

AIM: The primary objective of this study was to elucidate the putative cell wall-associated targets of compound 6i, a glycoconjugate of eugenol, in Aspergillus fumigatus, while also evaluating its toxicity and assessing histopathologic alterations in the liver, heart, and kidney of compound 6i-treated embryos using an in ovo model. METHOD: To achieve this aim, compound 6i was synthesized, and a series of biochemical assays were performed to determine its impact on the fungal cell wall. Additionally, qRT-PCR and LC-MS/MS analyses were conducted to investigate changes in gene and protein expression profiles associated with melanin biosynthesis, conidiation, siderophore production, transcriptional regulation of ß-glucan biosynthesis, and calcineurin activity in A. fumigatus. RESULTS: The experimental findings revealed that compound 6i exhibited notable antifungal activity against A. fumigatus by perturbing cell wall integrity, hindering ergosterol, glucan, and chitin biosynthesis, and inhibiting catalase production. Moreover, relative gene expression and proteomic analyses demonstrated that compound 6i exerted both down-regulatory and up-regulatory effects on several crucial genes and proteins involved in the aforementioned fungal processes. Furthermore, increased expression of oxidative stress-related proteins was observed in the presence of compound 6i. Notably, the glycoconjugate of eugenol did not elicit cytotoxicity in the liver, heart, and kidney of chick embryos. CONCLUSION: The current investigation elucidated the multifaceted mechanisms by which compound 6i exerts its antifungal effects against A. fumigatus, primarily through targeting cell wall components and signaling pathways. These findings underscore the potential of the eugenol glycoconjugate as a promising antifungal candidate, warranting further exploration and development for combating A. fumigatus infections.

Sequencing and de novo transcriptome assembly for discovering regulators of gene expression in Jack (Artocarpus heterophyllus).

Jack (Artocarpus heterophyllus) is a multipurpose fruit-tree species with minimal genomic resources. The study reports developing comprehensive transcriptome data containing 80,411 unigenes with an N50 value of 1265 bp. We predicted 64,215 CDSs from the unigenes and annotated and functionally categorized them into the biological process (23,230), molecular function (27,149), and cellular components (17,284). From 80,411 unigenes, we discovered 16,853 perfect SSRs with 192 distinct repeat motif types reiterating 4 to 22 times. Besides, we identified 2741 TFs from 69 TF families, 53 miRNAs from 19 conserved miRNA families, 25,953 potential lncRNAs, and placed three functional eTMs in different lncRNA-miRNA pairs. The regulatory networks involving genes, TFs, and miRNAs identified several regulatory and regulated nodes providing insight into miRNAs' gene associations and transcription factor-mediated regulation. The comparison of expression patterns of some selected miRNAs vis-à-vis their corresponding target genes showed an inverse relationship indicating the possible miRNA-mediated regulation of the genes.

Transcriptional Regulators Controlling Virulence in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a pathogen capable of colonizing virtually every human tissue. The host colonization competence and versatility of this pathogen are powered by a wide array of virulence factors necessary in different steps of the infection process. This includes factors involved in bacterial motility and attachment, biofilm formation, the production and secretion of extracellular invasive enzymes and exotoxins, the production of toxic secondary metabolites, and the acquisition of iron. Expression of these virulence factors during infection is tightly regulated, which allows their production only when they are needed. This process optimizes host colonization and virulence. In this work, we review the intricate network of transcriptional regulators that control the expression of virulence factors in P. aeruginosa, including one- and two-component systems and σ factors. Because inhibition of virulence holds promise as a target for new antimicrobials, blocking the regulators that trigger the production of virulence determinants in P. aeruginosa is a promising strategy to fight this clinically relevant pathogen.

Isoeugenol affects expression pattern of conidial hydrophobin gene RodA and transcriptional regulators MedA and SomA responsible for adherence and biofilm formation in Aspergillus fumigatus.

Aspergillus fumigatus is one of the major pathogenic fungal species, causing life-threatening infections. Due to a limited spectrum of available antifungals, exploration of new drug targets as well as potential antifungal molecules has become pertinent. Rodlet layer plays an important role in adherence of fungal conidia to hydrophobic cell surfaces in host, which also leads to A. fumigatus biofilm formation, contributing factor to fungal pathogenicity. From decades, natural sources have been known for the development of new active molecules. The present study investigates effect of isoeugenol on genes responsible for hydrophobins (RodA), adhesion as well as biofilm formation (MedA and SomA) of A. fumigatus. Minimum inhibitory concentrations (MIC and IC50) of isoeugenol against A. fumigatus were determined using broth microdilution assay. The IC50 results showed reduced hydrophobicity and biofilm formation as well as eradication after treatment with the compound and electron micrograph data corroborated these findings. The qRT-PCR showed a significant downregulation of genes RodA, MedA, SomA and pksP involved in hydrophobicity and biofilm formation. SwissADME studies potentiated drug-like propensity for isoeugenol which formed four hydrogen bonds with low binding energy (- 4.54 kcal/mol) at the catalytic site of RodA protein studied via AutoDock4. Hence, the findings conclude that isoeugenol inhibits conidial hydrophobicity and biofilm formation of A. fumigatus and further investigations are warranted in this direction.

Transcriptome analysis of North American sweet birch (Betula lenta) revealed a higher expression of genes involved in the biosynthesis of secondary metabolites than European silver birch (B. pendula).

The North American Betula lenta L. (sweet birch) has been used for medicinal reasons for centuries by native Americans. Although sophisticated technologies have rapidly been developed, a large information gap has been observed regarding genetic regulators of medicinally important compounds in sweet birch. Very little is known on the different genes involved in secondary metabolic biosynthesis in sweet birch. To gain a deeper insight into genetic factors, we performed a transcriptome analysis of each three biological samples from different independent trees of sweet and European silver birch (B. pendula Roth). This allowed us to precisely quantify the transcripts of about 24,000 expressed genes including 29 prominent candidate genes putatively involved in the biosynthesis of secondary metabolites like terpenoids, and aromatic benzoic acids. A total number of 597 genes were differentially expressed between B. lenta and B. pendula, while 264 and 210 genes showed upregulation in the bark and leaf of B. lenta, respectively. Moreover, we identified 39 transcriptional regulatory elements, involved in secondary metabolite biosynthesis, upregulated in B. lenta. Our study demonstrated the potential of RNA sequencing to identify candidate genes interacting in secondary metabolite biosynthesis in sweet birch. The candidate genes identified in this study could be subjected to genetic engineering to functionally characterize them in sweet birch. This knowledge can be beneficial to the increase of therapeutically important compounds.

Progress on the GntR family transcription regulators in bacteria.

In bacteria, GntR family transcription regulators are the widespread family of transcription factors. Members of this family consist of two functional domains, a conserved N-terminal DNA-binding domain that contains a typical helix-turn-helix (HTH) motif and a C-terminal effector-binding or oligomerization domain. Usually, the amino acid sequences of N-terminal DNA-binding domains are highly conserved, but differ in the C-terminal effector-binding or oligomerization domains. In the past several decades, many GntR family transcription regulators have been characterized in a number of bacteria. These regulators control a variety of cellular processes such as cell motility, glucose metabolism, bacterial resistance, pathogenesis and virulence. In this review, we summarized the discovery, C-terminal domains, biological function and regulation mode of GntR family transcription regulators. This review will help researchers to obtain more knowledge about the functions and mechanisms of the GntR family transcriptional regulatory factors.

A molecular signature for CD8+ T cells from visceral leishmaniasis patients.

CD8+ T-cell function is compromised in chronic diseases such as visceral leishmaniasis (VL). However, little is known about the changes in gene expression that cause CD8+ T-cell dysfunction during VL. We used targeted transcriptional profiling of peripheral blood CD8+ T cells from VL patients pre- and post-anti-parasitic drug treatment, and compared them with the same cell population from healthy endemic controls to assess their activation, differentiation and functional status during disease. We found a predominance of downregulated immune genes in CD8+ T cells from VL patients. However, genes encoding several notable immune checkpoint molecules, including LAG-3, TIM-3 and CTLA-4, cytolytic molecules, such as granzymes A, B and H and perforin, as well as SOCS3, STAT1, JAK2 and JAK3 cytokine signalling genes were found to be increasingly expressed by VL patient CD8+ T cells. Additional studies confirmed increased expression of the inhibitory receptors LAG3 and TIM3 on VL patient CD8+ T cells, thereby identifying these molecules as potential targets to improve antigen-specific CD8+ T-cell responses during disease.

Identification of a GntR family regulator BusRTha and its regulatory mechanism in the glycine betaine ABC transport system of Tetragenococcus halophilus.

Glycine betaine is one of the most effective compatible solutes of the halophilic lactic acid bacterium Tetragenococcus halophilus, the transportation of which is essential for its survival under salinity stress condition. In the current study, we attempted to define a glycine betaine ABC transporter system of T. halophilus, busATha, which plays an important role in adapting to salinity condition. The expression of busATha enhanced the growth of the recombinant strain under high salinity. BusRTha, a transcription regulator that represses the expression of busATha, was characterized, and the repression was abrogated under high salinity. The binding of the regulator was demonstrated through electrophoretic mobility shift assays, and the binding sites were characterized as 5'-AAA(T/G)TGAC(C/A)(G/A)T(C/A)C-3'. This is the first studied transcription regulator of T. halophilus, and our findings provide insights into the molecular mechanism of halophilic life and tools for further application of halophiles as chassis in industrial biotechnology.

The helix-loop-helix protein id1 controls stem cell proliferation during regenerative neurogenesis in the adult zebrafish telencephalon.

The teleost brain has the remarkable ability to generate new neurons and to repair injuries during adult life stages. Maintaining life-long neurogenesis requires careful management of neural stem cell pools. In a genome-wide expression screen for transcription regulators, the id1 gene, encoding a negative regulator of E-proteins, was found to be upregulated in response to injury. id1 expression was mapped to quiescent type I neural stem cells in the adult telencephalic stem cell niche. Gain and loss of id1 function in vivo demonstrated that Id1 promotes stem cell quiescence. The increased id1 expression observed in neural stem cells in response to injury appeared independent of inflammatory signals, suggesting multiple antagonistic pathways in the regulation of reactive neurogenesis. Together, we propose that Id1 acts to maintain the neural stem cell pool by counteracting neurogenesis-promoting signals.

Rugged fitness landscapes minimize promiscuity in the evolution of transcriptional repressors.

How a protein's function influences the shape of its fitness landscape, smooth or rugged, is a fundamental question in evolutionary biochemistry. Smooth landscapes arise when incremental mutational steps lead to a progressive change in function, as commonly seen in enzymes and binding proteins. On the other hand, rugged landscapes are poorly understood because of the inherent unpredictability of how sequence changes affect function. Here, we experimentally characterize the entire sequence phylogeny, comprising 1,158 extant and ancestral sequences, of the DNA-binding domain (DBD) of the LacI/GalR transcriptional repressor family. Our analysis revealed an extremely rugged landscape with rapid switching of specificity, even between adjacent nodes. Further, the ruggedness arises due to the necessity of the repressor to simultaneously evolve specificity for asymmetric operators and disfavors potentially adverse regulatory crosstalk. Our study provides fundamental insight into evolutionary, molecular, and biophysical rules of genetic regulation through the lens of fitness landscapes.

Yeast One-Hybrid Screening for Transcription Factors of IbbHLH2 in Purple-Fleshed Sweet Potato.

The transcription factor IbbHLH2 has been identified as involved in the biosynthesis of anthocyanins in purple-flesh sweet potatoes. However, little is known about the upstream transcription regulators of the promoter of IbbHLH2 in terms of their involvement in anthocyanin biosynthesis. For this study, the transcription regulators of the promoter of IbbHLH2 were screened via yeast one-hybrid assays in purple-fleshed sweet potato storage roots. Seven proteins, namely IbERF1, IbERF10, IbEBF2, IbPDC, IbPGP19, IbUR5GT, and IbDRM, were screened as upstream binding proteins of the promoter of IbbHLH2. The interactions between the promoter and these upstream binding proteins were verified using dual-luciferase reporter and yeast two-hybrid assays. Furthermore, the gene expression levels of transcription regulators, transcription factors, and structural genes involved in the anthocyanin biosynthesis of different root stages of purple and white-fleshed sweet potatoes were analyzed via real-time PCR. The obtained results indicate that IbERF1 and IbERF10 are key transcription regulators of the promoter of IbbHLH2 and are involved in anthocyanin biosynthesis in purple-fleshed sweet potatoes.

Yeast One-Hybrid Screening for Regulators of IbWD40 in Purple-Fleshed Sweet Potato (Ipomoea batatas [L] Lam.).

BACKGROUND: The transcription regulator IbWD40 is known to be involved in anthocyanin biosynthesis in purple-flesh sweet potato (Ipomoea batatas). However, little is known about the upstream transcription regulators on the promoter of IbWD40. METHODS: Yeast one-hybrid screening was performed on the storage roots of purple-fleshed sweet potato to identity upstream transcription regulators on the promoter of IbWD40. Luciferase reporter assays and Yeast one-hybrid assays were used to verify these upstream binding proteins interacted with the promoter. Real-time PCR was used to analyze the gene expression of upstream transcription regulators, transcription factors, and structural genes involved in anthocyanin biosynthesis in different root stages of purple-fleshed and white-fleshed sweet potato. RESULTS: IbERF1, IbERF10, IbEBF2, IbPDC, IbPGP19, IbUR5GT, IbDRM, IbPPA and IbERF73 were identified as candidate binding proteins for the promoter of IbWD40. Furthermore, IbERF1, IbERF10 and IbERF73 were identified as upstream transcription regulators on the promoter of IbWD40 involved in anthocyanin biosynthesis. CONCLUSIONS: IbERF1, IbERF10 and IbERF73 were identified as transcription regulators on the promoter of IbWD40, which is involved in the regulation of anthocyanin biosynthesis in purple-fleshed sweet potato.

Targeted Treatment and Immunotherapy in High-risk and Relapsed/ Refractory Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia is the most frequent pediatric malignancy in children, comprising 30% of all pediatric malignancies; adult ALL comprises 5% of all ALL cases, which have a 186.6 per 1 million incidence. In pediatric ALL (pALL), on which this review focuses, approximately 1 in 285 children are diagnosed with cancer before the age of 20, and approximately 1 in 530 young adults between the ages of 20 and 39 years old is a childhood cancer survivor. The survival probability in pALL is now very high, approximately 80-90%. Thus, the most important is to improve supportive care and treatment based on relapse risk, optimally being based on the genetic feature of malignant cells. Improvements made by now are mainly the classifying of subgroups based on genetic characteristics such as aneuploidy or translocation and aligning them with treatment response. Relevant genetic changes in ALL pathogenesis are transcription regulators of lymphoid development (PAX5, IKZF1, EBF1, and LEF1) and/or coactivators (TBL1XR1 and ERG), lymphoid signaling (BTLA, and CD200 TOX), and tumor suppressor genes (CDKN2A, CDKN2B, RB1, and TP53). This review aims to summarize treatment strategies inhibiting tyrosine kinases, influencing different signaling pathways, BCL inhibitors, and anti-CD therapy (anti-cluster differentiation therapy) in pALL. CAR T-cell therapy (chimeric antigen receptors T-cell therapy) is under research and requires further development.

Immunohistochemical expression of transcription factors PAX5, OCT2, BCL6 and transcription regulator P53 in Non-Hodgkin lymphomas: A diagnostic cross-sectional study.

Background: Non-Hodgkin lymphoma represents a heterogeneous group of tumors that constitute the seventh most common malignancy. Immunohistochemistry plays a major role in the detection of specific cell receptors. Transcription factors are a heterogeneous group of genes that play a critical role in the commitment, differentiation, and proliferation of specific cell types. Methods: Paraffin-embedded tissue sections of non-Hodgkin lymphoma cases were selected, classified, and evaluated before staining with immunohistochemical markers (PAX5, OCT2, BCL6, and P53). Expression of the aforementioned markers was compared with histological subtypes and grades of lymphoma cases. Means of expression were also compared among histological subtypes. Results: A total of 55 cases of NHL including 26 cases of low-grade lymphomas and 29 cases of high-grade lymphomas were included in the study. DLBCL and FL were the most common subtypes of high-grade and low-grade lymphomas respectively. Both PAX5 and OCT2 were positive in 44 cases of NHL (80%) including all cases of B-cell lymphomas. BCL6 and P53 demonstrated positive expression in 29.1% and 67.3% respectively. Interestingly, we found a significant association between the histological subtypes and the aforementioned markers (P-value<0.05). Discussion: Expression of PAX5, OCT2, BCL, and P53 played a major role in the diagnosis and grading of non-Hodgkin lymphomas in our study. Both PAX5 and OCT2 provided more accuracy and specificity in the diagnosis of B-cell neoplasms compared to the classical B-cell markers. BCL6 expression reflected its role in germinal center formation in normal and malignant lymphoid tissues, and expression of P53 mirrored the accumulation of gene mutations in more aggressive lymphoma subtypes. Conclusion: In this manuscript, we aimed to present a unique study that highlights the immunohistochemical expression of all the aforementioned factors among various histological subtypes of non-Hodgkin lymphomas with disparities in histological aggressiveness, highlighting a promising diagnostic and prognostic panel for non-Hodgkin lymphomas.

The Transcription Regulator YgeK Affects Biofilm Formation and Environmental Stress Resistance in Avian Pathogenic Escherichia coli.

Avian pathogenic Escherichia coli (APEC) is one of the most common pathogens in poultry and a potential gene source of human extraintestinal pathogenic E. coli (ExPEC), leading to serious economic losses in the poultry industry and public health concerns. Exploring the pathogenic mechanisms underpinning APEC and the identification of new targets for disease prevention and treatment are warranted. YgeK is a transcriptional regulator in APEC and is localized to the type III secretion system 2 of E. coli. In our previous work, the transcription factor ygeK significantly affected APEC flagella formation, bacterial motility, serum sensitivity, adhesion, and virulence. To further explore ygeK functions, we evaluated its influence on APEC biofilm formation and resistance to environmental stress. Our results showed that ygeK inactivation decreased biofilm formation and reduced bacterial resistance to environmental stresses, including acid and oxidative stress. In addition, the multi-level regulation of ygeK in APEC was analyzed using proteomics, and associations between differentially expressed proteins and the key targets of ygeK were investigated. Overall, we identified ygeK's new function in APEC. These have led us to better understand the transcriptional regulatory ygeK and provide new clues about the pathogenicity of APEC.

Transcriptional Regulation of the Multiple Resistance Mechanisms in Salmonella-A Review.

The widespread use of antibiotics, especially those with a broad spectrum of activity, has resulted in the development of multidrug resistance in many strains of bacteria, including Salmonella. Salmonella is among the most prevalent causes of intoxication due to the consumption of contaminated food and water. Salmonellosis caused by this pathogen is pharmacologically treated using antibiotics such as fluoroquinolones, ceftriaxone, and azithromycin. This foodborne pathogen developed several molecular mechanisms of resistance both on the level of global and local transcription modulators. The increasing rate of antibiotic resistance in Salmonella poses a significant global concern, and an improved understanding of the multidrug resistance mechanisms in Salmonella is essential for choosing the suitable antibiotic for the treatment of infections. In this review, we summarized the current knowledge of molecular mechanisms that control gene expression related to antibiotic resistance of Salmonella strains. We characterized regulators acting as transcription activators and repressors, as well as two-component signal transduction systems. We also discuss the background of the molecular mechanisms of the resistance to metals, regulators of multidrug resistance to antibiotics, global regulators of the LysR family, as well as regulators of histone-like proteins.

Metabolic circuits and gene regulators in polyhydroxyalkanoate producing organisms: Intervention strategies for enhanced production.

Worldwide worries upsurge concerning environmental pollutions triggered by the accumulation of plastic wastes. Biopolymers are promising candidates for resolving these difficulties by replacing non-biodegradable plastics. Among biopolymers, polyhydroxyalkanoates (PHAs), are natural polymers that are synthesized and accumulated in a range of microorganisms, are considered as promising biopolymers since they have biocompatibility, biodegradability, and other physico-chemical properties comparable to those of synthetic plastics. Consequently, considerable research have been attempted to advance a better understanding of mechanisms related to the metabolic synthesis and characteristics of PHAs and to develop native and recombinant microorganisms that can proficiently produce PHAs comprising desired monomers with high titer and productivity for industrial applications. Recent developments in metabolic engineering and synthetic biology applied to enhance PHA synthesis include, promoter engineering, ribosome-binding site (RBS) engineering, development of synthetic constructs etc. This review gives a brief overview of metabolic routes and regulators of PHA production and its intervention strategies.

Factors Determining the Susceptibility of Bacteria to Antibacterial Photodynamic Inactivation.

Photodynamic inactivation of microorganisms (aPDI) is an excellent method to destroy antibiotic-resistant microbial isolates. The use of an exogenous photosensitizer or irradiation of microbial cells already equipped with endogenous photosensitizers makes aPDI a convenient tool for treating the infections whenever technical light delivery is possible. Currently, aPDI research carried out on a vast repertoire of depending on the photosensitizer used, the target microorganism, and the light delivery system shows efficacy mostly on in vitro models. The search for mechanisms underlying different responses to photodynamic inactivation of microorganisms is an essential issue in aPDI because one niche (e.g., infection site in a human body) may have bacterial subpopulations that will exhibit different susceptibility. Rapidly growing bacteria are probably more susceptible to aPDI than persister cells. Some subpopulations can produce more antioxidant enzymes or have better performance due to efficient efflux pumps. The ultimate goal was and still is to identify and characterize molecular features that drive the efficacy of antimicrobial photodynamic inactivation. To this end, we examined several genetic and biochemical characteristics, including the presence of individual genetic elements, protein activity, cell membrane content and its physical properties, the localization of the photosensitizer, with the result that some of them are important and others do not appear to play a crucial role in the process of aPDI. In the review, we would like to provide an overview of the factors studied so far in our group and others that contributed to the aPDI process at the cellular level. We want to challenge the question, is there a general pattern of molecular characterization of aPDI effectiveness? Or is it more likely that a photosensitizer-specific pattern of molecular characteristics of aPDI efficacy will occur?

Thyroid Hormone Receptor α1 Mutants Impair B Lymphocyte Development in a Mouse Model.

Background: Mutations of the thyroid hormone receptor α (THRA) gene cause resistance to thyroid hormone (RTHα). RTHα patients exhibit very mild abnormal thyroid function test results (serum triiodothyronine can be high-normal to high; thyroxine normal to low; thyrotropin is normal or mildly raised) but manifest hypothyroid symptoms with growth retardation, delayed bone development, and anemia. Much has been learned about the in vivo molecular actions in TRα1 mutants affecting abnormal growth, bone development, and anemia by using a mouse model of RTHα (Thra1PV/+ mice). However, it is not clear whether TRα1 mutants affect lymphopoiesis in RTHα patients. The present study addressed the question of whether TRα1 mutants could cause defective lymphopoiesis. Methods: We assessed lymphocyte abundance in the peripheral circulation and in the lymphoid organs of Thra1PV/+ mice. We evaluated the effect of thyroid hormone on B cell development in the bone and spleen of these mice. We identified key transcription factors that are directly regulated by TRα1 in the regulation of B cell development. Results: Compared with wild-type mice, a significant reduction in B cells, but not in T cells, was detected in the peripheral circulation, bone marrow, and spleen of Thra1PV/+ mice. The expression of key transcription regulators of B cell development, such as Ebf1, Tcf3, and Pax5, was significantly decreased in the bone marrow and spleen of Thra1PV/+ mice. We further elucidated that the Ebf1 gene, essential for lineage specification in the early B cell development, was directly regulated by TRα1. Thus, mutations of TRα1 could impair B cell development in the bone marrow via suppression of key regulators of B lymphopoiesis. Conclusions: Analysis of lymphopoiesis in a mouse model of RTHα showed that B cell lymphopoiesis was suppressed by TRα1 mutations. The suppressed development of B cells was, at least in part, via inhibition of the expression of key regulators, Ebf1, Tcf3, and Pax5, by TRα1 mutations. These findings suggest that the mutations of the THRA gene in patients could lead to B cell deficiency.