The Experts below are selected from a list of 117774 Experts worldwide ranked by ideXlab platform
Weiwen Wang - One of the best experts on this subject based on the ideXlab platform.
-
adolescent social defeat induced alterations in social behavior and cognitive flexibility in adult mice effects of Developmental Stage and social condition
Frontiers in Behavioral Neuroscience, 2016Co-Authors: Fang Zhang, Sanna Yuan, Feng Shao, Weiwen WangAbstract:Negative social experiences during adolescence increase the risk of psychiatric disorders in adulthood. Using “resident-intruder” stress, the present study aimed to investigate the effects of adolescent social defeat on emotional and cognitive symptoms associated with psychiatric disorders during adulthood and the effects of the Developmental Stage and social condition on this process. In experiment 1, animals were exposed to social defeat or manipulation for 10 days during early adolescence (EA, PND 28-37), late adolescence (LA, PND 38-47), and adulthood (ADULT, PND 70-79) and then singly housed until the behavioral tests. Behaviors, including social avoidance of the defeat context and cortically mediated cognitive flexibility in an attentional set-shifting task (AST), were assessed during the week following stress or after 6 weeks during adulthood. We determined that social defeat induced significant and continuous social avoidance across age groups at both time points. The mice that experienced social defeat during adulthood exhibited short-term impairments in reversal learning on the AST that dissipated after 6 weeks. In contrast, social defeat during EA but not LA induced a delayed deficit in extra-dimensional set-shifting in adulthood but not during adolescence. In experiment 2, we further examined the effects of social condition (isolation or social housing after stress) on the alterations induced by social defeat during EA in adult mice. The adult mice that had experienced stress during EA exhibited social avoidance similar to the avoidance identified in experiment 1 regardless of the isolation or social housing after the stress. However, social housing after the stress ameliorated the cognitive flexibility deficits induced by early adolescent social defeat in the adult mice, and the social condition had no effect on cognitive function. These findings suggest that the effects of social defeat on emotion and cognitive function are differentially affected by the Developmental Stage and social condition. EA may comprise a particularly sensitive Developmental period in which social defeat may produce a delayed impairment in cognitive flexibility during adulthood, and the social condition following stress appears to play an important intermediary role in the development of these cognitive deficits.
-
adolescent social defeat induced alterations in social behavior and cognitive flexibility in adult mice effects of Developmental Stage and social condition
Frontiers in Behavioral Neuroscience, 2016Co-Authors: Fang Zhang, Sanna Yuan, Feng Shao, Weiwen WangAbstract:Negative social experiences during adolescence increase the risk of psychiatric disorders in adulthood. Using "resident-intruder" stress, the present study aimed to investigate the effects of adolescent social defeat on emotional and cognitive symptoms associated with psychiatric disorders during adulthood and the effects of the Developmental Stage and social condition on this process. In Experiment 1, animals were exposed to social defeat or manipulation for 10 days during early adolescence (EA, postnatal days [PND] 28-37), late adolescence (LA, PND 38-47), and adulthood (ADULT, PND 70-79) and then singly housed until the behavioral tests. Behaviors, including social avoidance of the defeat context and cortically mediated cognitive flexibility in an attentional set-shifting task (AST), were assessed during the week following stress or after 6 weeks during adulthood. We determined that social defeat induced significant and continuous social avoidance across age groups at both time points. The mice that experienced social defeat during adulthood exhibited short-term impairments in reversal learning (RL) on the AST that dissipated after 6 weeks. In contrast, social defeat during EA but not LA induced a delayed deficit in extra-dimensional set-shifting (EDS) in adulthood but not during adolescence. In Experiment 2, we further examined the effects of social condition (isolation or social housing after stress) on the alterations induced by social defeat during EA in adult mice. The adult mice that had experienced stress during EA exhibited social avoidance similar to the avoidance identified in Experiment 1 regardless of the isolation or social housing after the stress. However, social housing after the stress ameliorated the cognitive flexibility deficits induced by early adolescent social defeat in the adult mice, and the social condition had no effect on cognitive function. These findings suggest that the effects of social defeat on emotion and cognitive function are differentially affected by the Developmental Stage and social condition. EA may comprise a particularly sensitive Developmental period in which social defeat may produce a delayed impairment in cognitive flexibility during adulthood, and the social condition following stress appears to play an important intermediary role in the development of these cognitive deficits.
Salvatore Loguercio - One of the best experts on this subject based on the ideXlab platform.
-
variable extent of lineage specificity and Developmental Stage specificity of cohesin and ccctc binding factor binding within the immunoglobulin and t cell receptor loci
Frontiers in Immunology, 2018Co-Authors: Salvatore Loguercio, Michael S. Krangel, Mauricio E Barajasmora, Hanyu Shih, Ann J FeeneyAbstract:CTCF is largely responsible for the 3D architecture of the genome through the creation of long-range chromatin loops. Cohesin is hypothesized to be the main driver of these long-range chromatin interactions by the process of loop extrusion. Here we performed ChIP-seq for CTCF and cohesin in 2 Stages each of T and B cell differentiation and examined the binding pattern in all 6 antigen receptor (AgR) loci in these lymphocyte progenitors and in mature T and B cells, ES cells and fibroblasts. The 4 large AgR loci have many bound CTCF sites, most of which are only occupied in lymphocytes, while only the CTCF sites at the end of each locus near the enhancers or J genes tend to be bound in non-lymphoid cells also. However, despite the generalized lymphocyte restriction of CTCF binding in AgR loci, the Igκ locus is the only locus that also shows significant lineage-specificity (T vs. B cells) and Developmental Stage-specificity (pre-B vs. pro-B) in CTCF binding. We show that cohesin binding shows greater lineage- and Stage-specificity than CTCF at most AgR loci, providing more specificity to the loops. We also show that the culture of pro-B cells in IL7, a common practice to expand the number of cells before ChIP-seq, results in a CTCF binding pattern resembling pre-B cells, as well as other epigenetic and transcriptional characteristics of pre-B cells. Analysis of the orientation of the CTCF sites show that all sites within the large V portions of the Igh and TCRβ loci have the same orientation. This suggests either a lack of requirement for convergent CTCF sites creating loops, or indicates an absence of any loops between CTCF sites within the V region portion of those loci but only loops to the convergent sites at the D-J-enhancer end of each locus. The V region portions of the Igκ and TCRα/δ loci, in contrast, have CTCF sites in both orientations, providing many options for creating CTCF-mediated convergent loops throughout the loci. CTCF/cohesin loops, along with transcription factors, drives contraction of AgR loci to facilitate the creation of a diverse repertoire of antibodies and TCRs.
-
Variable Extent of Lineage-Specificity and Developmental Stage-Specificity of Cohesin and CCCTC-Binding Factor Binding Within the Immunoglobulin and T Cell Receptor Loci
Frontiers Media S.A., 2018Co-Authors: Salvatore Loguercio, Michael S. Krangel, Hanyu Shih, Mauricio E. Barajas-mora, Ann J FeeneyAbstract:CCCTC-binding factor (CTCF) is largely responsible for the 3D architecture of the genome, in concert with the action of cohesin, through the creation of long-range chromatin loops. Cohesin is hypothesized to be the main driver of these long-range chromatin interactions by the process of loop extrusion. Here, we performed ChIP-seq for CTCF and cohesin in two Stages each of T and B cell differentiation and examined the binding pattern in all six antigen receptor (AgR) loci in these lymphocyte progenitors and in mature T and B cells, ES cells, and fibroblasts. The four large AgR loci have many bound CTCF sites, most of which are only occupied in lymphocytes, while only the CTCF sites at the end of each locus near the enhancers or J genes tend to be bound in non-lymphoid cells also. However, despite the generalized lymphocyte restriction of CTCF binding in AgR loci, the Igκ locus is the only locus that also shows significant lineage-specificity (T vs. B cells) and Developmental Stage-specificity (pre-B vs. pro-B) in CTCF binding. We show that cohesin binding shows greater lineage- and Stage-specificity than CTCF at most AgR loci, providing more specificity to the loops. We also show that the culture of pro-B cells in IL7, a common practice to expand the number of cells before ChIP-seq, results in a CTCF-binding pattern resembling pre-B cells, as well as other epigenetic and transcriptional characteristics of pre-B cells. Analysis of the orientation of the CTCF sites show that all sites within the large V portions of the Igh and TCRβ loci have the same orientation. This suggests either a lack of requirement for convergent CTCF sites creating loops, or indicates an absence of any loops between CTCF sites within the V region portion of those loci but only loops to the convergent sites at the D-J-enhancer end of each locus. The V region portions of the Igκ and TCRα/δ loci, by contrast, have CTCF sites in both orientations, providing many options for creating CTCF-mediated convergent loops throughout the loci. CTCF/cohesin loops, along with transcription factors, drives contraction of AgR loci to facilitate the creation of a diverse repertoire of antibodies and T cell receptors
Frank Grosveld - One of the best experts on this subject based on the ideXlab platform.
-
hs5 of the human β globin locus control region a Developmental Stage specific border in erythroid cells
The EMBO Journal, 2003Co-Authors: Albert W K Wai, Sara Pruzina, Sjaak Philipsen, Nynke Gillemans, Selina Raguzbolognesi, Gaetano Zafarana, Dies Meijer, Frank GrosveldAbstract:Elements with insulator/border activity have been characterized most extensively in Drosophila melanogaster. In vertebrates, the first example of such an element was provided by a hypersensitive site of the chicken beta-globin locus, cHS4. It has been proposed that the homologous site in humans, HS5, functions as a border of the human beta-globin locus. Here, we have characterized HS5 of the human beta-globin locus control region. We have examined its tissue-specificity and assessed its insulating properties in transgenic mice using a lacZ reporter assay. Most importantly, we have tested its enhancer blocking activity in the context of the full beta-globin locus. Our results show that HS5 is erythroid-specific rather than ubiquitous in human tissues. Furthermore, HS5 does not fulfil the criteria of a general in vivo insulator in the transgene protection assay. Finally, a HS5 conditional deletion from the complete locus demonstrates that HS5 has no discernable activity in adult erythroid cells. Surprisingly, HS5 functions as an enhancer blocker in embryonic erythroid cells. We conclude that HS5 is a Developmental Stage-specific border in erythroid cells.
Stuart H Orkin - One of the best experts on this subject based on the ideXlab platform.
-
polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a Developmental Stage specific manner
Cell Stem Cell, 2014Co-Authors: Huafeng Xie, Stuart H Orkin, Jessie Haoru Hsu, Minh Nguyen, Yuko Fujiwara, Cong PengAbstract:Recent studies point to a pivotal role of Polycomb repressive complex 2 (PRC2) in stem cell function and cancer. Loss-of-function approaches targeting individual PRC2 subunits have, however, generated findings that are difficult to reconcile. Here, we prevent assembly of both Ezh1- and Ezh2-containing PRC2 complexes by conditional deletion of Eed, a core subunit, and assess hematopoiesis. We find that deletion of Eed exhausts adult bone marrow hematopoietic stem cells (HSCs), although fetal liver HSCs are produced in normal numbers. Eed-null neonatal HSCs express HSC signature genes but are defective in maintenance and differentiation. Comparative gene expression profiling revealed that neonatal and adult HSCs lacking Eed upregulated gene sets of conflicting pathways. Deletion of Cdkn2a, a PRC2 target gene, in Eed-null mice enhances hematopoietic stem/progenitor cell (HSPC) survival but fails to restore HSC functions. Taken together, our findings define Developmental-Stage-specific requirements for canonical PRC2 complexes in normal HSC function.
-
combinatorial assembly of Developmental Stage specific enhancers controls gene expression programs during human erythropoiesis
Developmental Cell, 2012Co-Authors: Jian Xu, Zhen Shao, Kimberly Glass, Daniel E Bauer, Luca Pinello, Ben Van Handel, John A Stamatoyannopoulos, Hanna K A Mikkola, Guocheng Yuan, Stuart H OrkinAbstract:Summary Gene-distal enhancers are critical for tissue-specific gene expression, but their genomic determinants within a specific lineage at different Stages of development are unknown. Here we profile chromatin state maps, transcription factor occupancy, and gene expression profiles during human erythroid development at fetal and adult Stages. Comparative analyses of human erythropoiesis identify Developmental Stage-specific enhancers as primary determinants of Stage-specific gene expression programs. We find that erythroid master regulators GATA1 and TAL1 act cooperatively within active enhancers but confer little predictive value for Stage specificity. Instead, a set of Stage-specific coregulators collaborates with master regulators and contributes to differential gene expression. We further identify and validate IRF2, IRF6, and MYB as effectors of an adult-Stage expression program. Thus, the combinatorial assembly of lineage-specific master regulators and transcriptional coregulators within Developmental Stage-specific enhancers determines gene expression programs and temporal regulation of transcriptional networks in a mammalian genome.
-
human fetal hemoglobin expression is regulated by the Developmental Stage specific repressor bcl11a
Blood, 2008Co-Authors: Vijay G Sankaran, Tobias F Menne, Thomas E Akie, Guillaume Lettre, Joel N Hirschhorn, Alan B Cantor, Stuart H OrkinAbstract:Numerous molecular approaches have been taken to elucidate the regulation of the human β-like globin genes, and particularly the “fetal” (γ- to β-) globin switch, given the role of fetal hemoglobin (HbF) levels on disease severity in the β-hemoglobin disorders. Despite these efforts, no Developmental Stage-specific nuclear regulators of HbF expression have been identified and validated. Recent genome-wide single nucleotide polymorphism (SNP) association studies by us and others have revealed novel loci that are significantly associated with HbF levels in normal, sickle cell, and thalassemia populations. One variant, lying within intron 2 of the chromosome 2 gene BCL11A, accounts for >10% of the variation in HbF levels. We have now tested the hypothesis that BCL11A, a zinc-finger transcription factor, serves as a Stage-specific regulator of HbF expression, rather than merely a genetic marker of HbF status. We found that BCL11A is expressed as two major isoforms (termed XL and L) in human erythroid progenitors. The level of BCL11A expression is inversely correlated with the expression of the HbF gene, γ-globin, in human erythroid cell types representative of different Developmental Stages. Expression of BCL11A is negligible in embryonic, and high in adult, erythroid cells. Correlation of SNP genotypes with levels of BCL11A RNA in cells derived from individuals of known genotypes indicates that the “high HbF” genotype is associated with reduced BCL11A expression. To better characterize its potential role in erythropoiesis and globin gene regulation, we identified interacting protein partners of BCL11A in erythroid cells through affinity purification and protein microsequencing. We found that the BCL11A protein exists in complexes with the nucleosome remodeling and histone deacetylase (NuRD) corepressor complex, as well as the erythroid transcription factors GATA-1 and FOG-1. Taken together, the genetic, Developmental, and biochemical data are most consistent with a model in which BCL11A functions as a repressor of γ-globin gene expression. To directly test this possibility, we modulated expression of BCL11A in primary human erythroid precursors expanded from adult CD34+ progenitors. Transient or persistent knockdown of BCL11A accomplished by siRNA or lentiviral shRNA delivery, respectively, led to robust induction of γ-globin gene expression. Importantly, down-regulation of BCL11A expression did not alter the differentiation state or global transcriptional profile of the cells, suggesting an effect on a limited number of targets, including the γ-globin gene. In summary, these studies establish BCL11A as a potent regulator of human globin switching. As an adult-Stage repressor, BCL11A represents a primary target for therapy aimed at reactivating HbF expression in patients with β-hemoglobin disorders. Our studies illustrate the power of an integrative approach to reveal the functional connection between a common genetic variant and a trait that serves as a prominent modifier of disease severity.
-
Developmental Stage selective effect of somatically mutated leukemogenic transcription factor gata1
Nature Genetics, 2005Co-Authors: Janhenning Klusmann, Frank J Godinho, Mireia Garrigacanut, Stuart H OrkinAbstract:Developmental Stage–selective effect of somatically mutated leukemogenic transcription factor GATA1
Akiyoshi Fukamizu - One of the best experts on this subject based on the ideXlab platform.
-
human β globin locus control region hs5 contains ctcf and Developmental Stage dependent enhancer blocking activity in erythroid cells
Molecular and Cellular Biology, 2003Co-Authors: Keiji Tanimoto, James Douglas Engel, Gary Felsenfeld, Akiko Sugiura, Akane Omori, Akiyoshi FukamizuAbstract:The human beta-globin locus contains five Developmentally regulated beta-type globin genes. All five genes depend on the locus control region (LCR), located at the 5' end of the locus, for abundant globin gene transcription. The LCR is composed of five DNase I-hypersensitive sites (HSs), at least a subset of which appear to cooperate to form a holocomplex in activating genes within the locus. We previously tested the requirement for proper LCR polarity by inverting it in human beta-globin yeast artificial chromosome transgenic mice and observed reduced expression of all the beta-type globin genes regardless of Developmental Stage. This phenotype clearly demonstrated an orientation-dependent activity of the LCR, although the mechanistic basis for the observed activity was obscure. Here, we describe genetic evidence demonstrating that human HS5 includes enhancer-blocking (insulator) activity that is both CTCF and Developmental Stage dependent. Curiously, we also observed an attenuating activity in HS5 that was specific to the epsilon-globin gene at the primitive Stage and was independent of the HS5 CTCF binding site. These observations demonstrate that the phenotype observed in the LCR-inverted locus was in part attributable to placing the HS5 insulator between the LCR HS enhancers (HS1 to HS4) and the promoter of the beta-globin gene.
