Unraveling the Sox4-orchestrated pro-B cell differentiation program: Intricate roles of the RAG and CK1e genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50067 | GEO | 2014/07/02
SECONDARY ACCESSION(S): PRJNA215933
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-07-02 | E-GEOD-50067 | biostudies-arrayexpress
Project description:One of the main objective of this study is to identify Sox4 controlled gene networks and their roles in progenitor B cells. Commitment of hematopoietic stem cells to B lineage precursors and development of B lineage precursors into mature B cells is attained through the coordinated function of multiple signaling networks, which are in turn controlled through stringent functioning of stage-specific transcription factors. Here, we describe the essential role of Sox4, an HMG (high mobility group)-box-containing transactivator, in B cell development. In the absence of Sox4, differentiation from pre-pro B to pro-B, from pro-B fraction B to pro-B fraction C and further to the immature B cell stage was severely impaired. Loss of differentiation was associated with reduced expression of Rag1 and Rag2 and markedly reduced DJ (diverse, joining) and VDJ (variable DJ) recombination at immunoglobulin heavy chain gene loci. We uncovered Sox4-regulated transcriptional circuits and a landscape of Sox4-chromatin interactions in pro-B cells. Sox4 ensured the negative regulation of Wnt signaling, which is critical for self-renewal of hematopoietic stem cells and early progenitors, by inducing one of its downstream effectors, casein kinase 1 epsilon. Our findings suggest that Sox4 orchestrates a unique transcriptional program and coordinates multilevel control in the differentiation of early-stage B cells. Total RNA isolated from triplicate samples were used for each cell type. Gene expression signatures were compared between Sox4fl/fl and Sox4fl/fl SE-Cre progenitor B cells (Loss-of-function array); p190 Bcr-Abl-immortalized Sox4fl/fl SE-Cre HA and Sox4fl/fl SE-Cre HA-Sox4 progenitor B cells (Gain-of-function array).
2014-07-02 | E-GEOD-50065 | biostudies-arrayexpress
Project description:Commitment of hematopoietic stem cells to B lineage precursors and development of B lineage precursors into mature B cells is attained through the coordinated function of multiple signaling networks, which are in turn controlled through stringent functioning of stage-specific transcription factors. Here, we describe the essential role of Sox4, an HMG (high mobility group)-box-containing transactivator, in B cell development. In the absence of Sox4, differentiation from pre-pro B to pro-B, from pro-B fraction B to pro-B fraction C and further to the immature B cell stage was severely impaired. Loss of differentiation was associated with reduced expression of Rag1 and Rag2 and markedly reduced DJ (diverse, joining) and VDJ (variable DJ) recombination at immunoglobulin heavy chain gene loci. We uncovered Sox4-regulated transcriptional circuits and a landscape of Sox4-chromatin interactions in pro-B cells. Sox4 ensured the negative regulation of Wnt signaling, which is critical for self-renewal of hematopoietic stem cells and early progenitors, by inducing one of its downstream effectors, casein kinase 1 epsilon. Our findings suggest that Sox4 orchestrates a unique transcriptional program and coordinates multilevel control in the differentiation of early-stage B cells. One sample of BAP-Sox4 bioChIP DNA and one sample of BAP-Sox4 input chromatin DNA were used.
2014-07-02 | E-GEOD-50066 | biostudies-arrayexpress
Project description:Commitment of hematopoietic stem cells to B lineage precursors and development of B lineage precursors into mature B cells is attained through the coordinated function of multiple signaling networks, which are in turn controlled through stringent functioning of stage-specific transcription factors. Here, we describe the essential role of Sox4, an HMG (high mobility group)-box-containing transactivator, in B cell development. In the absence of Sox4, differentiation from pre-pro B to pro-B, from pro-B fraction B to pro-B fraction C and further to the immature B cell stage was severely impaired. Loss of differentiation was associated with reduced expression of Rag1 and Rag2 and markedly reduced DJ (diverse, joining) and VDJ (variable DJ) recombination at immunoglobulin heavy chain gene loci. We uncovered Sox4-regulated transcriptional circuits and a landscape of Sox4-chromatin interactions in pro-B cells. Sox4 ensured the negative regulation of Wnt signaling, which is critical for self-renewal of hematopoietic stem cells and early progenitors, by inducing one of its downstream effectors, casein kinase 1 epsilon. Our findings suggest that Sox4 orchestrates a unique transcriptional program and coordinates multilevel control in the differentiation of early-stage B cells.
2014-07-02 | GSE50066 | GEO
Project description:One of the main objective of this study is to identify Sox4 controlled gene networks and their roles in progenitor B cells. Commitment of hematopoietic stem cells to B lineage precursors and development of B lineage precursors into mature B cells is attained through the coordinated function of multiple signaling networks, which are in turn controlled through stringent functioning of stage-specific transcription factors. Here, we describe the essential role of Sox4, an HMG (high mobility group)-box-containing transactivator, in B cell development. In the absence of Sox4, differentiation from pre-pro B to pro-B, from pro-B fraction B to pro-B fraction C and further to the immature B cell stage was severely impaired. Loss of differentiation was associated with reduced expression of Rag1 and Rag2 and markedly reduced DJ (diverse, joining) and VDJ (variable DJ) recombination at immunoglobulin heavy chain gene loci. We uncovered Sox4-regulated transcriptional circuits and a landscape of Sox4-chromatin interactions in pro-B cells. Sox4 ensured the negative regulation of Wnt signaling, which is critical for self-renewal of hematopoietic stem cells and early progenitors, by inducing one of its downstream effectors, casein kinase 1 epsilon. Our findings suggest that Sox4 orchestrates a unique transcriptional program and coordinates multilevel control in the differentiation of early-stage B cells.
2014-07-02 | GSE50065 | GEO
Project description:Commitment of hematopoietic stem cells to B lineage precursors and subsequent development of B lineage precursors into mature B cells is stringently controlled by stage-specific transcription factors. In this study, we used integrated genetic approaches and systematically determined the role of Sry-related high mobility group box (Sox) 4 and the underlying molecular mechanisms in early B-cell development. We found that Sox4 coordinates multilevel controls in the differentiation of early stage B cells. At the molecular level, Sox4 orchestrates a unique gene regulatory program, and its function was predominantly mediated through a conventional Sox4-binding motif as well as an unconventional GA-binding protein ? chain binding motif. Our integrated gene network and functional analysis indicated that Sox4 functions as a bimodular transcription factor and ensures B lineage precursor differentiation through 2 distinct mechanisms. It positively induces gene rearrangements at immunoglobulin heavy chain gene loci by transcriptionally activating the Rag1 and Rag2 genes and negatively regulates Wnt signaling, which is critical for self-renewal, by inducing the expression of casein kinase 1 ?. Our findings illustrate that Sox4 mediates critical fine-tuning of the 2 opposing forces in early B-cell development and also set forth a model for characterization of critical genes whose deficiency, like Sox4 deficiency, is detrimental to this process.
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Project description:Global transcriptome reprogramming during spermatogenesis ensures timely expression of factors in each phase of male germ cell differentiation. Spermatocytes and spermatids require particularly extensive reprogramming of gene expression to switch from mitosis to meiosis and to support gamete morphogenesis. Here, we uncovered an extensive alternative splicing program during this transmeiotic differentiation. Notably, intron retention was largely the most enriched pattern, with spermatocytes showing generally higher levels of retention compared with spermatids. Retained introns are characterized by weak splice sites and are enriched in genes with strong relevance for gamete function. Meiotic intron-retaining transcripts (IRTs) were exclusively localized in the nucleus. However, differently from other developmentally regulated IRTs, they are stable RNAs, showing longer half-life than properly spliced transcripts. Strikingly, fate-mapping experiments revealed that IRTs are recruited onto polyribosomes days after synthesis. These studies reveal an unexpected function for regulated intron retention in modulation of the timely expression of select transcripts during spermatogenesis.
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Project description:CREB3 proteins comprise a set of ER-localized bZip transcription factors defined by the presence of a transmembrane domain. They are regulated by inter-compartmental transport, Golgi cleavage and nuclear transport where they promote appropriate transcriptional responses. Although CREB3 proteins play key roles in differentiation, inflammation and metabolism, a general framework relating their defining features to these diverse activities is lacking. We identify unique features of CREB3 organization including the ATB domain, which we show it is essential for transcriptional activity. This domain is absent in all other human bZip factors, but conserved in Drosophila CREBA, which controls secretory pathway genes (SPGs). Furthermore, each of the five human CREB3 factors was capable of activating SPGs in Drosophila, dependent upon the ATB domain. Expression of the CREB3 protein, CREB-H, in 293 cells, upregulated genes involved in secretory capacity, extracellular matrix formation and lipid metabolism and increased secretion of specific cargos. In liver cells, which normally express CREB-H, the active form specifically induced secretion of apolipoproteins, including ApoA-IV, ApoAI, consistent with data implicating CREB-H in metabolic homeostasis. Based on these data and other recent studies, we propose a general role for the CREB3 family in regulating secretory capacity, with particular relevance to specialized cargos.
| S-EPMC3593995 | biostudies-literature
Project description:The development of mature B cells from hematopoietic stem cells is a strictly orchestrated process involving multiple regulatory genes. The transcription factor Sox4 is required for this process, but its role has not been systematically studied, and the underlying mechanisms remain unknown. To determine when and how Sox4 functions in the stepwise process of B cell development, we used mice harboring conditional null alleles for Sox4 and a Cre transgene. Sox4 deletion in hematopoietic stem cells almost entirely eliminated pro-B cells in both fetal livers and adult bone marrow, resulting in a severe deficiency in later stage B cells, including circulating mature B cells. Sox4-deficient pro-B cells, particularly those expressing the stem cell factor receptor c-Kit, readily underwent apoptosis, and even more so when c-Kit activity was inhibited by imatinib. C-Kit-expressing pro-B cells showed decreased activation of the c-Kit downstream protein Src upon Sox4 deletion. Likewise, the level of the anti-apoptotic Bcl2 protein was decreased in residual pro-B cells, and its restoration using a Bcl2 transgene allowed not only partial rescue of pro-B cell survival but also B cell maturation in the absence of Sox4. Our findings indicate that Sox4 is required for the survival of pro-B cells and may functionally interact with c-Kit and Bcl2.
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Project description:Neuroblastoma (NB), which is considered to be caused by the differentiation failure of neural crest cells, is the most common extracranial malignant solid tumor in children. The degree of tumor differentiation in patients with NB is closely correlated with the survival rate. To explore the potential targets that mediate NB cell differentiation, we analyzed four microarray datasets from GEO, and the overlapping down- or upregulated DEGs were displayed using Venn diagrams. SOX4 was one of the overlapping upregulated DEGs and was confirmed by RT-qPCR and Western blot in ATRA-treated NGP, SY5Y, and BE2 cells. To clarify whether SOX4 was the target gene regulating NB cell differentiation, the correlation between the expression of SOX4 and the survival of clinical patients was analyzed via the R2 database, SOX4 overexpression plasmids and siRNAs were generated to change the expression of SOX4, RT-qPCR and Western blot were performed to detect SOX4 expression, cell confluence or cell survival was detected by IncuCyte Zoom or CCK8 assay, immunocytochemistry staining was performed to detect cells' neurites, and a cell cycle analysis was implemented using Flow cytometry after PI staining. The results showed that the survival probabilities were positively correlated with SOX4 expression, in which overexpressing SOX4 inhibited NB cell proliferation, elongated the cells' neurite, and blocked the cell cycle in G1 phase, and that knockdown of the expression of SOX4 partially reversed the ATRA-induced inhibition of NB cell proliferation, the elongation of the cells' neurites, and the blocking of the cell cycle in the G1 phase. These indicate that SOX4 may be a target to induce NB cell differentiation.
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