Differential Gene Expression in Circulating T-Cells in Long-Term Adolescent/Young Adult Hodgkin Lymphoma (AYAHL) Survivors and Their Unaffected Twins

Background: We and others have demonstrated persistent differences in T cell function and cytokine responses in adolescent/ young adult Hodgkin lymphoma (AYAHL) survivors and their family members. To identify the transcription control pathways involved, we examined mRNA profiles from 17 pairs of long term AYA HL survivors and their unaffected twins. Methods: Blood samples were collected remotely from AYAHL survivors and their like-sex unaffected co-twin controls and shipped to the Epeldegui laboratory at UCLA. B and T cells were negatively separated using magnetic beads. RNA was extracted and sequenced using a high-efficiency mRNA-targeted assay system (Lexogen QuantSeq 3' FWD), with an average 6.7 million reads per sample mapped to the hg38 human transcriptome (99%) using the STAR aligner. Raw read counts for each gene transcript were normalized to transcripts per million total mapped reads and log2 transformed for analysis using linear statistical models including a random effect of twin pair. Analyses examined average expression of pre-specified sets of 17 genes in general immunologic activation (i.e., AP-1- and NF-kB-family transcripts) and 28 Type I IFN-responsive genes (e.g., IFI-, OAS-, and MX-family), as well as TELiS promoter-based bioinformatics analyses of all genes showing >2-fold empirical differences in gene expression (focusing on activation-induced transcription factors, NF-kB and AP-1, and Type 1 interferon-related IRF transcription factors). Body mass index, history of therapeutic radiation, zygosity, sex, age at diagnosis and age at blood collection were included in the model. Results: The average age at diagnosis was 25 years with blood collected 33 years post-diagnosis. In T-cells, AYAHL survivors showed marginally lower expression of 12 activation-induced genes (average 0.41-fold, p = .038) and markedly lower expression of 28 Type 1 interferon-related genes (average 0.33-fold, p < .001) relative to their unaffected co-twins. B cells showed similar reductions in activation-induced genes (0.33-fold, p < .001) but no difference in Type 1 interferon genes (1.02-fold, p =. 942). Promoter-based bioinformatics analyses of all 151 genes found to be differentially expressed by >2-fold in T cells between AYAHL survivors and their unaffected co-twin controls implicated IRF-family transcription factors in mediating observed differences, with IRF3 showing the most significant signal of decreased activity (0.68-fold, p = .059). We also identified marked up-regulation of multiple GATA family transcription factors (GATA3: p < .001; GATA1: p = .009; GATA2: p = .032). Conclusions: Transcriptional indicators of immunologic activation and Type 1 interferon activity show persistent down-regulation in T lymphocytes from long-term adult AYAHL survivors compared to their unaffected like-sex co-twin controls. Incidental findings also identified persistent activation of other gene regulatory pathways mediating T-cell differentiation (e.g., GATA family). We have previously demonstrated higher Epstein-Barr virus (EBV) copy number in AYAHL long-term survivors compared to their unaffected co-twin controls, as well as lower levels of circulating interleukin-12, consistent with a decrease in the ability to control viral replication. The GATA family plays a major role in commitment to T cell lineage (GATA3) and upregulation of the T-helper-type 2 response, and possibly in control of EBV viral infection (GATA2), processes relevant to AYAHL. These differences further support the premise that abnormalities in T-cells play a strong role in etiology, pathogenesis, and survivorship. Disclosures No relevant conflicts of interest to declare.

GATA3 is essential for separating patterning domains during facial morphogenesis

Neural crest cells (NCCs) within the mandibular and maxillary prominences of the first pharyngeal arch are initially competent to respond to signals from either region. However, mechanisms that are only partially understood establish developmental tissue boundaries to ensure spatially correct patterning. In the Hinge and Caps model of facial development, signals from both ventral prominences (the caps) pattern the adjacent tissues while the intervening region, referred to as the maxillomandibular junction (the hinge), maintains separation of the mandibular and maxillary domains. One cap signal is GATA3, a member of the GATA family of zinc-finger transcription factors with a distinct expression pattern in the ventral-most part of the mandibular and maxillary portions of the first arch. Here we show that disruption of Gata3 in mouse embryos leads to craniofacial microsomia and syngnathia (bony fusion of the upper and lower jaws) that results from changes in BMP4 and FGF8 gene regulatory networks within NCCs near the maxillomandibular junction. GATA3 is thus a crucial component in establishing the network of factors that functionally separate the upper and lower jaws during development.

Genome-Wide Identification, Phylogenetic and Expression Pattern Analysis of GATA Family Genes in Cucumber (Cucumis sativus L.)

GATA transcription factors are a class of transcriptional regulatory proteins that contain a characteristic type-IV zinc finger DNA-binding domain, which play important roles in plant growth and development. The GATA gene family has been characterized in various plant species. However, GATA family genes have not been identified in cucumber. In this study, 26 GATA family genes were identified in cucumber genome, whose physicochemical characteristics, chromosomal distributions, phylogenetic tree, gene structures conserved motifs, cis-regulatory elements in promoters, homologous gene pairs, downstream target genes were analyzed. Tissue expression profiles of cucumber GATA family genes exhibited that 17 GATA genes showed constitutive expression, and some GATA genes showed tissue-specific expression patterns. RNA-seq analysis of green and virescent leaves revealed that seven GATA genes might be involved in the chloroplast development and chlorophyll biosynthesis. Importantly, expression patterns analysis of GATA genes in response to abiotic and biotic stresses indicated that some GATA genes respond to either abiotic stress or biotic stress, some GATA genes such as Csa2G162660, Csa3G017200, Csa3G165640, Csa4G646060, Csa5G622830 and Csa6G312540 were simultaneously functional in resistance to abiotic and biotic stresses. Overall, this study will provide useful information for further analysis of the biological functions of GATA factors in cucumber.

Cloning and expression analysis of GATA1 gene in Carassius auratus red var

BackgroundGATA1 is a key transcription factor in the GATA family, and promotes the differentiation and maturation of red blood cell, which is essential for normal hematopoiesis.ResultsOur results showed that the cDNA sequence ofGATA1 was 2730 bp long encoding 443 amino acids. qRT-PCR analysis demonstrated thatGATA1 had the highest expression in testis (T), followed by pituitary (P) and spleen (S).GATA1 gene expression inC. auratusred var. embryo from the neuroblast stage (N) to the embryo hatching (H) changes continuously; and the gene expression levels of nonylphenol (NP)-treated and those of control embryos were significantly different. Moreover, Methylation levels ofGATA1gene in NP-treated embryos were higher than those in control embryos, indicating that NP affectedGATA1methylation.ConclusionsOur study provides cues for further studying the roles ofGATA1 gene in fish development, and suggested a potential molecular mechanism by which NP leads to abnormal development of fish embryos.

Development and Carcinogenesis: Roles of GATA Factors in the Sympathoadrenal and Urogenital Systems

The GATA family of transcription factors consists of six proteins (GATA1-6) that control a variety of physiological and pathological processes. In particular, GATA2 and GATA3 are coexpressed in a number of tissues, including in the urogenital and sympathoadrenal systems, in which both factors participate in the developmental process and tissue maintenance. Furthermore, accumulating studies have demonstrated that GATA2 and GATA3 are involved in distinct types of inherited diseases as well as carcinogenesis in diverse tissues. This review summarizes our current knowledge of how GATA2 and GATA3 participate in the transcriptional regulatory circuitry during the development of the sympathoadrenal and urogenital systems, and how their dysregulation results in the carcinogenesis of neuroblastoma, renal urothelial, and gynecologic cancers.

GATA3 is essential for separating patterning domains during facial morphogenesis

Neural crest cells (NCCs) within the mandibular and maxillary portions of the first pharyngeal arch are initially competent to respond to signals from either region. However, mechanisms that are only partially understood establish developmental tissue boundaries to ensure spatially correct patterning. In the Hinge and Caps model of facial development, signals from both ventral prominences, referred to as the caps, pattern the adjacent tissues while the intervening region, known as the hinge, maintains separation of the mandibular and maxillary domains. One cap signal is GATA3, a member of the GATA family of zinc-finger transcription factors with a distinct expression pattern in the ventral-most part of the mandibular and maxillary portions of the first arch. Here we show that disruption of Gata3 in mouse embryos leads to hemifacial microsomia, facial bone hypoplasia and syngnathia (bony fusion of the upper and lower jaws). These changes are preceded by gene expression changes in post-migratory NCCs around the maxillomandibular junction (the hinge). GATA3 is thus a crucial component in establishing the network of factors that functionally separate the upper and lower jaws during development.Summary StatementLoss of Gata3 leads to BMP-mediated disruption of Fgf8 expression at the maxillomandibular junction during development, resulting in later fusion of the upper and lower jaws.

Cloning and Expression Analysis of GATA1 gene in Carassius auratus red var.

Background: GATA1 is a key transcription factor in the GATA family, and promotes the differentiation and maturation of red blood cell, which is essential for normal hematopoiesis.Results: Our results showed that the cDNA sequence of GATA1 was 2730 bp long encoding 443 amino acids. qRT-PCR analysis demonstrated that GATA1 had the highest expression in testis(T), followed by pituitary(P) and spleen(S). GATA1 gene expression in C. auratus red var. embryo from the neuroblast stage (N) to the embryo hatching(H) changes continuously; and the gene expression levels of nonylphenol (NP)-treated and those of control embryos were significantly different. Moreover, Methylation levels of GATA1 gene in NP-treated embryos were higher than those in control embryos, indicating that NP affected GATA1 methylation.Conclusions: Our study provides cues for further studying the roles of GATA1 gene in fish development, and suggested a potential molecular mechanism by which NP leads to abnormal development of fish embryos.

Cloning and Expression Analysis of GATA1 gene in Carassius auratus red var.

Background GATA1 is a key transcription factor in the GATA family, and promotes the differentiation and maturation of red blood cell, which is essential for normal hematopoiesis. Results Our results showed that the cDNA sequence of GATA1 was 2730 bp long encoding 443 amino acids. qRT-PCR analysis demonstrated that GATA1 had the highest expression in testis(T), followed by pituitary(P) and spleen(S). The expression of GATA1 gene in C auratus red var. embryo from the neuroblast stage (N) to the embryo hatching(H); and the gene expression levels of NP-treated and control embryos were significantly different. Methylation results in NP-treated and control embryos indicated that NP affected the methylation level of GATA1. NP increases the methylation level of GATA1 gene in embryos. Conclusions Our study provides important information for further studying the function of GATA1 gene in fish development and the molecular mechanism of NP leading to abnormal development of fish embryos.