[GATA factor-related hematopoietic neoplasms].

GATA1, GATA2, and GATA3, collectively known as hematopoietic GATA factors, play a central role in the transcription factor network that governs hematopoietic homeostasis. Dysfunction of these factors leads to various hematopoietic disorders. Aberrant function of GATA1 factor, crucial in erythrocyte and megakaryocyte differentiation, not only causes anemia and thrombocytopenia, but also triggers erythroid leukemia and acute megakaryoblastic leukemia. Similarly, GATA2 factor expression is dynamic in the hematopoietic hierarchy, and dysfunction of GATA2 factor contributes not only to dysfunction of the myeloid and lymphoid lineages but also to the development of diverse hematopoietic neoplasms such as myelodysplastic syndromes, acute myeloid leukemia, and myeloproliferative neoplasms. GATA3, critical for T-lymphocyte differentiation, is relevant to lymphocytic leukemia. This review discusses hematopoietic disorders caused by aberrant GATA transcription functions, with a particular emphasis on hematopoietic malignancies.

Endogenous small molecule effectors in GATA transcription factor mechanisms governing biological and pathological processes.

Transcriptional mechanisms establish and maintain complex genetic and protein networks to control cell state transitions. The hematopoietic transcription factor GATA1 is a master regulator of erythropoiesis and megakaryopoiesis, and human GATA1 genetic variants cause anemia and megakaryoblastic leukemia. Multiomic analyses revealed that GATA1 controls expression of transporters and metabolic enzymes that dictate intracellular levels of endogenous small molecules, including heme, metal ions, and sphingolipids. Besides its canonical function as a hemoglobin component, heme facilitates or antagonizes GATA1 function to regulate erythropoiesis via mechanisms dependent or independent of the heme-binding transcription factor BTB domain and CNC homology 1 (BACH1). GATA1 regulates the expression of genes encoding heme biosynthetic enzymes and BACH1. GATA1 maintains homeostasis of bioactive ceramides during erythroid differentiation by regulating genes encoding sphingolipid metabolic enzymes. Disrupting ceramide homeostasis impairs critical cytokine signaling and is detrimental to erythroid cells. During erythroid maturation, GATA1 induces a zinc transporter switch that favors export versus import, thus dictating the intracellular zinc level, erythroblast survival, and differentiation. In aggregate, these studies support an emerging paradigm in which GATA factor-dependent transcriptional mechanisms control the intracellular levels of endogenous small molecules and small molecule-dependent feedback loops that serve as vital effectors of transcription factor activity, genome function, and cell state transitions.

The role of GATA family transcriptional factors in haematological malignancies: A review.

GATA transcriptional factors are zinc finger DNA binding proteins that regulate transcription during development and cell differentiation. The 3 important GATA transcription factors GATA1, GATA2 and GATA3 play essential role in the development and maintenance of hematopoietic systems. GATA1 is required for the erythroid and Megakaryocytic commitment during hematopoiesis. GATA2 is crucial for the proliferation and survival of early hematopoietic cells, and is also involved in lineage specific transcriptional regulation as the dynamic partner of GATA1. GATA3 plays an essential role in T lymphoid cell development and immune regulation. As a result, mutations in gene encoding the GATA transcription factor or alteration in the protein expression level or their function have been linked to a variety of human haematological malignancies. This review presents a summary of recent understanding of how the disrupted biological function of GATA may contribute to hematologic diseases.

Gatad2b, associated with the neurodevelopmental syndrome GAND, plays a critical role in neurodevelopment and cortical patterning.

GATAD2B (GATA zinc finger domain containing 2B) variants are associated with the neurodevelopmental syndrome GAND, characterized by intellectual disability (ID), infantile hypotonia, apraxia of speech, epilepsy, macrocephaly and distinct facial features. GATAD2B encodes for a subunit of the Nucleosome Remodeling and Histone Deacetylase (NuRD) complex. NuRD controls transcriptional programs critical for proper neurodevelopment by coupling histone deacetylase with ATP-dependent chromatin remodeling activity. To study mechanisms of pathogenesis for GAND, we characterized a mouse model harboring an inactivating mutation in Gatad2b. Homozygous Gatad2b mutants die perinatally, while haploinsufficient Gatad2b mice exhibit behavioral abnormalities resembling the clinical features of GAND patients. We also observed abnormal cortical patterning, and cellular proportions and cell-specific alterations in the developmental transcriptome in these mice. scRNAseq of embryonic cortex indicated misexpression of genes key for corticogenesis and associated with neurodevelopmental syndromes such as Bcl11b, Nfia and H3f3b and Sox5. These data suggest a crucial role for Gatad2b in brain development.

Iron homeostasis proteins Grx4 and Fra2 control activity of the Schizosaccharomyces pombe iron repressor Fep1 by facilitating [2Fe-2S] cluster removal.

The Bol2 homolog Fra2 and monothiol glutaredoxin Grx4 together play essential roles in regulating iron homeostasis in Schizosaccharomyces pombe. In vivo studies indicate that Grx4 and Fra2 act as coinhibitory partners that inactivate the transcriptional repressor Fep1 in response to iron deficiency. In Saccharomyces cerevisiae, Bol2 is known to form a [2Fe-2S]-bridged heterodimer with the monothiol Grxs Grx3 and Grx4, with the cluster ligands provided by conserved residues in Grx3/4 and Bol2 as well as GSH. In this study, we characterized this analogous [2Fe-2S]-bridged Grx4-Fra2 complex in S. pombe by identifying the specific residues in Fra2 that act as ligands for the Fe-S cluster and are required to regulate Fep1 activity. We present spectroscopic and biochemical evidence confirming the formation of a [2Fe-2S]-bridged Grx4-Fra2 heterodimer with His66 and Cys29 from Fra2 serving as Fe-S cluster ligands in S. pombe. In vivo transcription and growth assays confirm that both His66 and Cys29 are required to fully mediate the response of Fep1 to low iron conditions. Furthermore, we analyzed the interaction between Fep1 and Grx4-Fra2 using CD spectroscopy to monitor changes in Fe-S cluster coordination chemistry. These experiments demonstrate unidirectional [2Fe-2S] cluster transfer from Fep1 to Grx4-Fra2 in the presence of GSH, revealing the Fe-S cluster dependent mechanism of Fep1 inactivation mediated by Grx4 and Fra2 in response to iron deficiency.

Transcriptome analysis of trembling aspen (Populus tremuloides) under nickel stress.

Plants have evolved heavy metal tolerance mechanisms to adapt and cope with nickel (Ni) toxicity. Decrypting whole gene expression of Trembling Aspen (Pinus tremuloides) under nickel stress could elucidate the nickel resistance/tolerance mechanisms. The main objectives of the present research were to 1) characterize the P. tremuloides transcriptome, and 2) compare gene expression dynamics between nickel-resistant and nickel-susceptible P. tremuloides genotypes with Whole Transcriptome (WT) sequencing. Illumina Sequencing generated 27-45 million 2X150 paired-end reads of raw data per sample. The alignment performed with StringTie Software added two groups of transcripts to the draft genome annotation. One group contained 32,677 new isoforms that match to 17,254 genes. The second group contained 17,349 novel transcripts that represent 16,157 novel genes. Overall, 52,987 genes were identified from which 36,770 genes were selected as differently expressed. With the high stringency (two-fold change, FDR value ≤ 0.05 and logFC value ≥1 (upregulated) or ≤ -1 (downregulated), after GSEA analysis and filtering for gene set size, 575 gene sets were upregulated and 146 were downregulated in nickel resistant phenotypes compared to susceptible genotypes. For biological process, genes associated with translation were significantly upregulated while signal transduction and cellular protein process genes were downregulated in resistant compared to susceptible genotypes. For molecular function, there was a significant downregulation of genes associated with DNA binding in resistant compared to susceptible lines. Significant upregulation was observed in genes located in ribosome while downregulation of genes in chloroplast and mitochondrion were preponderant in resistant genotypes compared to susceptible. Hence, from a whole transcriptome level, an upregulation in ribosomal and translation activities was identified as the main response to Ni toxicity in the resistant plants. More importantly, this study revealed that a metal transport protein (Potrs038704g29436 -ATOX1-related copper transport) was among the top upregulated genes in resistant genotypes when compared to susceptible plants. Other identified upregulated genes associated with abiotic stress include genes coding for Dirigent Protein 10, GATA transcription factor, Zinc finger protein, Auxin response factor, Bidirectional sugar transporter, and thiamine thiazole synthase.

A GATA-type transcription factor SreA affects manganese susceptibility by regulating the expression of iron uptake-related genes.

SreA has been identified as a GATA-type transcription factor that represses iron uptake to avoid iron excess during iron sufficiency. However, knowledge about whether SreA also affects the homeostasis of other divalent metal ions is limited. In this study, by screening Aspergillus fumigatus transcription factor deletion mutant libraries, we demonstrate that the sreA deletion mutant shows the greatest tolerance to MnCl2 among the tested divalent metal ions. Fe and Mn stimuli are able to enhance the expression of SreA with the different time-dependent manner, while the expression of SreA contributes to Mn2+ tolerance. Lack of SreA results in abnormally increased expression of a series of siderophore biosynthesis genes and iron transport-related genes, especially under MnCl2 treatment. Further mechanistic exploration indicated that lack of SreA exacerbates abnormal iron uptake, and iron excess inhibits cellular Mn content; thus, deletion of sreA results in Mn tolerance. Thus, findings in this study have demonstrated a new unexplored function for the transcription factor SreA in regulation of the Mn2+ tolerance.

Functional mechanisms of TRPS1 in disease progression and its potential role in personalized medicine.

The gene of transcriptional repressor GATA binding 1 (TRPS1), as an atypical GATA transcription factor, has received considerable attention in a plethora of physiological and pathological processes, and may become a promising biomarker for targeted therapies in diseases and tumors. However, there still lacks a comprehensive exploration of its functions and promising clinical applications. Herein, relevant researches published in English from 2000 to 2022 were retrieved from PubMed, Google Scholar and MEDLINE, concerning the roles of TRPS1 in organ differentiation and tumorigenesis. This systematic review predominantly focused on summarizing the structural characteristics and biological mechanisms of TRPS1, its involvement in tricho-rhino-phalangeal syndrome (TRPS), its participation in the development of multiple tissues, the recent advances of its vital features in metabolic disorders as well as malignant tumors, in order to prospect its potential applications in disease detection and cancer targeted therapy. From the clinical perspective, the deeply and thoroughly understanding of the complicated context-dependent and cell-lineage-specific mechanisms of TRPS1 would not only gain novel insights into the complex etiology of diseases, but also provide the fundamental basis for the development of therapeutic drugs targeting both TRPS1 and its critical cofactors, which would facilitate individualized treatment.

Insights Into the Roles of GATA Factors in Mammalian Testis Development and the Control of Fetal Testis Gene Expression.

Defining how genes get turned on and off in a correct spatiotemporal manner is integral to our understanding of the development, differentiation, and function of different cell types in both health and disease. Testis development and subsequent male sex differentiation of the XY fetus are well-orchestrated processes that require an intricate network of cell-cell communication and hormonal signals that must be properly interpreted at the genomic level. Transcription factors are at the forefront for translating these signals into a coordinated genomic response. The GATA family of transcriptional regulators were first described as essential regulators of hematopoietic cell differentiation and heart morphogenesis but are now known to impact the development and function of a multitude of tissues and cell types. The mammalian testis is no exception where GATA factors play essential roles in directing the expression of genes crucial not only for testis differentiation but also testis function in the developing male fetus and later in adulthood. This minireview provides an overview of the current state of knowledge of GATA factors in the male gonad with a particular emphasis on their mechanisms of action in the control of testis development, gene expression in the fetal testis, testicular disease, and XY sex differentiation in humans.

The chromatin remodelling ATPase BRAHMA interacts with GATA-family transcription factor GNC to regulate flowering time in Arabidopsis.

BRAHMA (BRM) is the ATPase of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodelling complex, which is indispensable for transcriptional inhibition and activation, associated with vegetative and reproductive development in Arabidopsis thaliana. Here, we show that BRM directly binds to the chromatin of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), which integrates multiple flowering signals to regulate floral transition, leading to flowering. In addition, genetic and molecular analysis showed that BRM interacts with GNC (GATA, NITRATE-INDUCIBLE, CARBON METABOLISM INVOLVED), a GATA transcription factor that represses flowering by directly repressing SOC1 expression. Furthermore, BRM is recruited by GNC to directly bind to the chromatin of SOC1. The transcript level of SOC1 is elevated in brm-3, gnc, and brm-3/gnc mutants, which is associated with increased histone H3 lysine 4 tri-methylation (H3K4Me3) but decreased DNA methylation. Taken together, our results indicate that BRM associates with GNC to regulate SOC1 expression and flowering time.

bfc, a novel serpent co-factor for the expression of croquemort, regulates efferocytosis in Drosophila melanogaster.

Efferocytosis is the process by which phagocytes recognize, engulf, and digest (or clear) apoptotic cells during development. Impaired efferocytosis is associated with developmental defects and autoimmune diseases. In Drosophila melanogaster, recognition of apoptotic cells requires phagocyte surface receptors, including the scavenger receptor CD36-related protein, Croquemort (Crq, encoded by crq). In fact, Crq expression is upregulated in the presence of apoptotic cells, as well as in response to excessive apoptosis. Here, we identified a novel gene bfc (booster for croquemort), which plays a role in efferocytosis, specifically the regulation of the crq expression. We found that Bfc protein interacts with the zinc finger domain of the GATA transcription factor Serpent (Srp), to enhance its direct binding to the crq promoter; thus, they function together in regulating crq expression and efferocytosis. Overall, we show that Bfc serves as a Srp co-factor to upregulate the transcription of the crq encoded receptor, and consequently boosts macrophage efferocytosis in response to excessive apoptosis. Therefore, this study clarifies how phagocytes integrate apoptotic cell signals to mediate efferocytosis.

Comprehensive Comparative Analysis of the GATA Transcription Factors in Four Rosaceae Species and Phytohormonal Response in Chinese Pear (Pyrus bretschneideri) Fruit.

The GATA gene family is one of the most important transcription factors (TFs). It extensively exists in plants, contributes to diverse biological processes such as the development process, and responds to environmental stress. Although the GATA gene family has been comprehensively and systematically studied in many species, less is known about GATA genes in Chinese pears (Pyrus bretschneideri). In the current study, the GATA gene family in the four Rosaceae genomes was identified, its structural characteristics identified, and a comparative analysis of its properties was carried out. Ninety-two encoded GATA proteins were authenticated in the four Rosaceae genomes (Pyrus bretschneideri, Prunus avium, Prunus mume, and Prunus persica) and categorized into four subfamilies (Ⅰ-Ⅳ) according to phylogeny. The majority of GATA genes contained one to two introns and conserved motif composition analysis revealed their functional divergence. Whole-genome duplications (WGDs) and dispersed duplication (DSD) played a key role in the expansion of the GATA gene family. The microarray indicated that, among P. bretschneideri, P. avium, P. mume and P. persica, GATA duplicated regions were more conserved between Pyrus bretschneideri and Prunus persica with 32 orthologous genes pairs. The physicochemical parameters, duplication patterns, non-synonymous (ka), and synonymous mutation rate (ks) and GO annotation ontology were performed using different bioinformatics tools. cis-elements respond to various phytohormones, abiotic/biotic stress, and light-responsive were found in the promoter regions of GATA genes which were induced via stimuli. Furthermore, subcellular localization of the PbGATA22 gene product was investigated, showing that it was present in the nucleus of tobacco (Nicotiana tabacum) epidermal cells. Finally, in silico analysis was performed on various organs (bud, leaf, stem, ovary, petal, and sepal) and different developmental stages of fruit. Subsequently, the expression profiles of PbGATA genes were extensively expressed under exogenous hormonal treatments of SA (salicylic acid), MeJA (methyl jasmonate), and ABA (abscisic acid) indicating that play important role in hormone signaling pathways. A comprehensive analysis of GATA transcription factors was performed through systematic biological approaches and comparative genomics to establish a theoretical base for further structural and functional investigations in Rosaceae species.

Non-mitochondrial aconitase regulates the expression of iron-uptake genes by controlling the RNA turnover process in fission yeast.

Aconitase, a highly conserved protein across all domains of life, functions in converting citrate to isocitrate in the tricarboxylic acid cycle. Cytosolic aconitase is also known to act as an iron regulatory protein in mammals, binding to the RNA hairpin structures known as iron-responsive elements within the untranslated regions of specific RNAs. Aconitase-2 (Aco2) in fission yeast is a fusion protein consisting of an aconitase and a mitochondrial ribosomal protein, bL21, residing not only in mitochondria but also in cytosol and the nucleus. To investigate the role of Aco2 in the nucleus and cytoplasm of fission yeast, we analyzed the transcriptome of aco2ΔN mutant that is deleted of nuclear localization signal (NLS). RNA sequencing revealed that the aco2ΔN mutation caused increase in mRNAs encoding iron uptake transporters, such as Str1, Str3, and Shu1. The half-lives of mRNAs for these genes were found to be significantly longer in the aco2ΔN mutant than the wild-type strain, suggesting the role of Aco2 in mRNA turnover. The three conserved cysteines required for the catalytic activity of aconitase were not necessary for this role. The UV cross-linking RNA immunoprecipitation analysis revealed that Aco2 directly bound to the mRNAs of iron uptake transporters. Aco2-mediated degradation of iron-uptake mRNAs appears to utilize exoribonuclease pathway that involves Rrp6 as evidenced by genetic interactions. These results reveal a novel role of non-mitochondrial aconitase protein in the mRNA turnover in fission yeast to fine-tune iron homeostasis, independent of regulation by transcriptional repressor Fep1.

Mesenchymal-to-epithelial transitions require tissue-specific interactions with distinct laminins.

Mesenchymal-to-epithelial transition (MET) converts cells from migratory mesenchymal to polarized epithelial states. Despite its importance for both normal and pathological processes, very little is known about the regulation of MET in vivo. Here we exploit midgut morphogenesis in Drosophila melanogaster to investigate the mechanisms underlying MET. We show that down-regulation of the EMT transcription factor Serpent is required for MET, but not sufficient, as interactions with the surrounding mesoderm are also essential. We find that midgut MET relies on the secretion of specific laminins via the CopII secretory pathway from both mesoderm and midgut cells. We show that secretion of the laminin trimer containing the Wingblister α-subunit from the mesoderm is an upstream cue for midgut MET, leading to basal polarization of αPS1 integrin in midgut cells. Polarized αPS1 is required for the formation of a monolayered columnar epithelium and for the apical polarization of αPS3, Baz, and E-Cad. Secretion of a distinct LamininA-containing trimer from midgut cells is required to reinforce the localization of αPS1 basally, and αPS3 apically, for robust repolarization. Our data suggest that targeting these MET pathways, in conjunction with therapies preventing EMT, may present a two-pronged strategy toward blocking metastasis in cancer.

Potential roles of condensin in genome organization and beyond in fission yeast.

The genome is highly organized hierarchically by the function of structural maintenance of chromosomes (SMC) complex proteins such as condensin and cohesin from bacteria to humans. Although the roles of SMC complex proteins have been well characterized, their specialized roles in nuclear processes remain unclear. Condensin and cohesin have distinct binding sites and mediate long-range and short-range genomic associations, respectively, to form cell cycle-specific genome organization. Condensin can be recruited to highly expressed genes as well as dispersed repeat genetic elements, such as Pol III-transcribed genes, LTR retrotransposon, and rDNA repeat. In particular, mitotic transcription factors Ace2 and Ams2 recruit condensin to their target genes, forming centromeric clustering during mitosis. Condensin is potentially involved in various chromosomal processes such as the mobility of chromosomes, chromosome territories, DNA reannealing, and transcription factories. The current knowledge of condensin in fission yeast summarized in this review can help us understand how condensin mediates genome organization and participates in chromosomal processes in other organisms.

Identification of potential key genes and pathways associated with the Pashmina fiber initiation using RNA-Seq and integrated bioinformatics analysis.

Pashmina goat (Capra hircus) is an economically important livestock species, which habitats the cold arid desert of the Ladakh region (India), and produces a princely animal fiber called Pashmina. The Pashmina goat has a double coat fleece as an adaptation to the very harsh cold winters the outer long coarse hair (guard hair) produced from primary hair follicles and the inner fine Pashmina fiber produced from secondary hair follicles. Pashmina fiber undergoes a circannual and synchronized growth cycle. In the present study, we analyzed transcriptome profiles from 10 different Pashmina goats during anagen and telogen to delineate genes and signaling pathways regulating active (anagen) and regressive (telogen) phases of the follicle growth. During anagen, 150 genes were expressed at significantly higher levels with log (FC) > 2 and padj < 0.05. The RNA seq results were subjected to qRT-PCR validation. Among the nine genes selected, the expression of HAS1, TRIB2, P2RX1. PRG4, CNR2, and MMP25 were significantly higher (p < 0.05) in the anagen phase, whereas MC4R, GIPC2, and CDO1 were significantly expressed (p < 0.05) in the telogen phase which supports and validates the gene expression pattern from the RNA-sequencing. Differentially expressed genes revealed that Pashmina fiber initiation is largely controlled by signaling pathways like Wnt, NF-Kappa, JAK-STAT, Hippo, MAPK, Calcium, and PI3K-Akt. Expression of genes from the Integrin family, Cell adhesion molecules, and ECM-receptors were observed to be at much higher levels during anagen. We identified key genes (IL36RN, IGF2, ITGAV, ITGA5, ITCCR7, CXCL5, C3, CCL19, and CXCR3) and a collagen cluster which might be tightly correlated with anagen-induction. The regulatory network suggests the potential role of RUNX3, NR2F1/2, and GATA family transcription factors in anagen-initiation and maintaining fiber quality in Pashmina goats.

Cross-linking mass spectrometry reveals the structural topology of peripheral NuRD subunits relative to the core complex.

The multi-subunit nucleosome remodeling and deacetylase (NuRD) complex consists of seven subunits, each of which comprises two or three paralogs in vertebrates. These paralogs define mutually exclusive and functionally distinct complexes. In addition, several proteins in the complex are multimeric, which complicates structural studies. Attempts to purify sufficient amounts of endogenous complex or recombinantly reconstitute the complex for structural studies have proven quite challenging. Until now, only substructures of individual domains or proteins and low-resolution densities of (partial) complexes have been reported. In this study, we comprehensively investigated the relative orientation of different subunits within the NuRD complex using multiple cross-link IP mass spectrometry (xIP-MS) experiments. Our results confirm that the core of the complex is formed by MTA, RBBP, and HDAC proteins. Assembly of a copy of MBD and GATAD2 onto this core enables binding of the peripheral CHD and CDK2AP proteins. Furthermore, our experiments reveal that not only CDK2AP1 but also CDK2AP2 interacts with the NuRD complex. This interaction requires the C terminus of CHD proteins. Our data provide a more detailed understanding of the topology of the peripheral NuRD subunits relative to the core complex. DATABASE: Proteomics data are available in the PRIDE database under the accession numbers PXD017244 and PXD017378.

A shared genetic contribution to breast cancer and schizophrenia.

An association between schizophrenia and subsequent breast cancer has been suggested; however the risk of schizophrenia following a breast cancer is unknown. Moreover, the driving forces of the link are largely unclear. Here, we report the phenotypic and genetic positive associations of schizophrenia with breast cancer and vice versa, based on a Swedish population-based cohort and GWAS data from international consortia. We observe a genetic correlation of 0.14 (95% CI 0.09-0.19) and identify a shared locus at 19p13 (GATAD2A) associated with risks of breast cancer and schizophrenia. The epidemiological bidirectional association between breast cancer and schizophrenia may partly be explained by the genetic overlap between the two phenotypes and, hence, shared biological mechanisms.

Chinese Yellow Rice Wine Processing with Reduced Ethyl Carbamate Formation by Deleting Transcriptional Regulator Dal80p in Saccharomyces cerevisiae.

Ethyl carbamate (EC) is a potential carcinogen that forms spontaneously during Chinese rice wine fermentation. The primary precursor for EC formation is urea, which originates from both external sources and arginine degradation. Urea degradation is suppressed by nitrogen catabolite repression (NCR) in Saccharomyces cerevisiae. The regulation of NCR is mediated by two positive regulators (Gln3p, Gat1p/Nil1p) and two negative regulators (Dal80p/Uga43p, Deh1p/Nil2p/GZF3p). DAL80 revealed higher transcriptional level when yeast cells were cultivated under nitrogen-limited conditions. In this study, when DAL80-deleted yeast cells were compared to wild-type BY4741 cells, less urea was accumulated, and genes involved in urea utilization were up-regulated. Furthermore, Chinese rice wine fermentation was conducted using dal80Δ cells; the concentrations of urea and EC were both reduced when compared to the BY4741 and traditional fermentation starter. The findings of this work indicated Dal80p is involved in EC formation possibly through regulating urea metabolism and may be used as the potential target for EC reduction.