Loss-of-function SLC30A2 mutants are associated with gut dysbiosis and alterations in intestinal gene expression in preterm infants

As essential structural components of ATP-dependent chromatin-remodeling complex, the nucleolus-localized actin-related proteins (ARPs) play critical roles in many biological processes. Among them, ARP4 is identified as an integral subunit of chromatin remodeling complex SWR1, which is conserved in yeast, humans and plants. It was shown that RNAi mediated knock-down of Arabidopsis thaliana ARP4 (AtARP4) could affect plant development, specifically, leading to early flowering. However, so far, little is known about how ARP4 functions in the SWR1 complex in plant. Here, we identified a loss-of-function mutant of AtARP4 with a single nucleotide change from glycine to arginine, which had significantly smaller leaf size. The results from the split luciferase complementation imaging (LCI) and yeast two hybrid (Y2H) assays confirmed its physical interaction with the scaffold and catalytic subunit of SWR1 complex, photoperiod-independent early flowering 1 (PIE1). Furthermore, mutation of AtARP4 caused altered transcription response of hundreds of genes, in which the number of up-regulated differentially expressed genes (DEGs) was much larger than those down-regulated. Although most DEGs in atarp4 are related to plant defense and response to hormones such as salicylic acid, overall, it has less overlapping with other swr1 mutants and the hta9 hta11 double-mutant. In conclusion, our results reveal that AtARP4 is important for plant growth and such an effect is likely attributed to its repression on gene expression, typically at defense-related loci, thus providing some evidence for the coordination of plant growth and defense, while the regulatory patterns and mechanisms are distinctive from other SWR1 complex components.

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The Drosophila dCREB-A gene is required for dorsal/ventral patterning of the larval cuticle

Development ◽

10.1242/dev.124.1.181 ◽

1997 ◽

Vol 124 (1) ◽

pp. 181-193 ◽

Cited By ~ 4

Author(s):

D.J. Andrew ◽

A. Baig ◽

P. Bhanot ◽

S.M. Smolik ◽

K.D. Henderson

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Signaling Cascades ◽

Loss Of Function ◽

Larval Cuticle ◽

Extracellular Signals ◽

Patterning Genes ◽

Lateral Structures ◽

Cuticular Structures

We report on the characterization of the first loss-of-function mutation in a Drosophila CREB gene, dCREB-A. In the epidermis, dCREB-A is required for patterning cuticular structures on both dorsal and ventral surfaces since dCREB-A mutant larvae have only lateral structures around the entire circumference of each segment. Based on results from epistasis tests with known dorsal/ventral patterning genes, we propose that dCREB-A encodes a transcription factor that functions near the end of both the DPP- and SPI-signaling cascades to translate the corresponding extracellular signals into changes in gene expression. The lateralizing phenotype of dCREB-A mutants reveals a much broader function for CREB proteins than previously thought.

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Thrombocytosis in preterm infants: a possible involvement of thrombopoietin receptor gene expression

Journal of Molecular Medicine ◽

10.1007/s00109-004-0619-z ◽

2005 ◽

Vol 83 (4) ◽

pp. 316-320 ◽

Cited By ~ 5

Author(s):

Hideki Nakayama ◽

Kenji Ihara ◽

Shunji Hikino ◽

Junko Yamamoto ◽

Taro Nagatomo ◽

...

Keyword(s):

Gene Expression ◽

Preterm Infants ◽

Receptor Gene ◽

Thrombopoietin Receptor ◽

Receptor Gene Expression

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How Gut Microbiota Supports Immunity, Growth and Development of Preterm Infants: A Narrative Review

Amerta Nutrition ◽

10.20473/amnt.v5i1sp.2021.14-20 ◽

2021 ◽

Vol 5 (1SP) ◽

pp. 14

Author(s):

Ariani Dewi Widodo

Keyword(s):

Gut Microbiota ◽

Human Milk ◽

Preterm Infants ◽

Premature Infants ◽

Growth And Development ◽

Gastrointestinal Microbiome ◽

Gut Dysbiosis ◽

Complex Ecosystem ◽

Full Enteral Feeding ◽

Lower Morbidity

ABSTRACTBackground: Gut microbiota, a complex ecosystem consisting of abundant microorganisms, plays a role in preterm infants’ immunity, growth, and development. Dysbiosis or disruption of the gut microbiota can precipitate various diseases, such as allergy or autoimmune disorders in premature infants. Purpose: This study aimed to review gut microbiota in preterm infants and its role in supporting the infants’ immunity, growth, and development. Discussion: Bifidobactericeae is the predominant microbiota in GI tract of preterm infants. However, various factors can influence this gut microbiota e.g., genetics, lifestyle of the mothers (smoking, diet, use of antibiotic, obesity), birth mode, type of feeding, and environmental factors. Gut dysbiosis can result in impaired immune system which predisposes the preterm infants to infections, even fatal adverse event. Furthermore, the growth and development might be affected as well as lead to various neurodevelopmental and psychiatric disorders. Human milk is a prebiotic source which can stimulate the growth of Baifidobactericeae and Bacteroidetes. If the human milk is inadequate or unavailable, the recommended interventions for gut dysbiosis in premature infants are probiotics, prebiotics, or both supplementations (synbiotics). The administration of prebiotics and probiotics associates with lower morbidity and death rates in preterm infants, as well as shorter duration of hospital stay and duration to achieve full enteral feeding. Conclusions: Immunity as well as growth and development of preterm infants are affected greatly by gut microbiota The less diverse microbiota in preterm infants’ gut predispose them to various health problems. Hence, this problem should be managed properly, one of which is prebiotic and probiotic supplementation Keywords: Gastrointestinal Microbiome, Premature, Immunity, Growth, Development

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Auxin methylation is required for differential growth inArabidopsis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1806565115 ◽

2018 ◽

Vol 115 (26) ◽

pp. 6864-6869 ◽

Cited By ~ 10

Author(s):

Mohamad Abbas ◽

Jorge Hernández-García ◽

Stephan Pollmann ◽

Sophia L. Samodelov ◽

Martina Kolb ◽

...

Keyword(s):

Gene Expression ◽

Auxin Transport ◽

Polar Auxin Transport ◽

Asymmetric Distribution ◽

Loss Of Function ◽

Differential Growth ◽

Specific Expression ◽

Auxin Homeostasis ◽

Auxin Distribution ◽

Gene Expression Levels

Asymmetric auxin distribution is instrumental for the differential growth that causes organ bending on tropic stimuli and curvatures during plant development. Local differences in auxin concentrations are achieved mainly by polarized cellular distribution of PIN auxin transporters, but whether other mechanisms involving auxin homeostasis are also relevant for the formation of auxin gradients is not clear. Here we show that auxin methylation is required for asymmetric auxin distribution across the hypocotyl, particularly during its response to gravity. We found that loss-of-function mutants inArabidopsis IAA CARBOXYL METHYLTRANSFERASE1(IAMT1) prematurely unfold the apical hook, and that their hypocotyls are impaired in gravitropic reorientation. This defect is linked to an auxin-dependent increase inPINgene expression, leading to an increased polar auxin transport and lack of asymmetric distribution of PIN3 in theiamt1mutant. Gravitropic reorientation in theiamt1mutant could be restored with either endodermis-specific expression ofIAMT1or partial inhibition of polar auxin transport, which also results in normalPINgene expression levels. We propose that IAA methylation is necessary in gravity-sensing cells to restrict polar auxin transport within the range of auxin levels that allow for differential responses.

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Association of KMT2C/D loss-of-function mutations with tumor infiltrating lymphocytes and response to immune checkpoint inhibitors in solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2587 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2587-2587

Author(s):

Ruiqi Liu ◽

Yanling Niu ◽

Xin Zhang ◽

Tonghui Ma

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

T Cells ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Tumor Infiltrating Lymphocytes ◽

Loss Of Function ◽

Cancer Types ◽

Immune Related Genes ◽

Infiltrating Lymphocytes

2587 Background: Dysregulation of HMTs plays an important role in tumorigenesis. KMT2C and KMT2D are enzymatically active scaffold proteins that form the core of mammalian COMPASS complexes, which methylate the histone 3 lysine 4. Both KMT2C and KMT2D are involved in the regulation of gene expression. Therefore, we explored the associations of KMT2C/D loss-of-function (LOF) mutations with the expression of immune-related genes, the levels of tumor infiltrating lymphocytes (TILs), and response to immune checkpoint inhibitors (ICIs). Methods: KMT2C/D LOF mutations were defined as nonsense, frameshift, splice site variants within consensus regions, start lost, and stop lost/gained variants. An ICIs treatment cohort from the MSKCC was used for exploring the associations between KMT2C/D LOF mutations and ICIs efficacy. The RNA-Seq data obtained from the TCGA cohort was used for analysis of gene expression and the levels of TILs using CIBERSORT. Results: In MSKCC pan-cancer dataset, patients with KMT2C/D LOF mutations had a relatively longer median overall survival (OS) compared to those with non-LOF mutations, although the result did not reach statistical significance (P = 0.0832). Then we analyzed the predictive roles of KMT2C/D LOF mutations for each cancer type. The results showed that the predictive role of KMT2C/D LOF mutations for the clinical efficacy of ICIs therapy was only observed in colorectal cancer (P = 0.045). However, we did not find the associations of KMT2C/D LOF mutations with ICIs efficacy in bladder cancer, breast cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, NSCLC, and esophagogastric cancer. Consistently, analysis of TILs in colorectal cancer revealed that KMT2C/D LOF was associated with increased infiltration of several types of immune cells, such as CD8+ T cells (P = 0.0001), activated NK cells (P = 0.0001), M1 macrophage (P = 0.0005), M2 macrophage (P = 0.0115), and neutrophils (P = 0.0209). Meanwhile, regulatory T cells (Tregs) (P = 0.0048) and M0 macrophage (P = 0.0043) were dramatically decreased in KMT2C/D LOF group for colorectal cancer. Moreover, there were no significant relationships between KMT2C/D LOF and the levels of TILs in other cancer types. Our data also demonstrated that KMT2C and KMT2D could regulate the expression of more than 30 immune-related genes in colorectal cancer. Conclusions: Our data indicated that KMT2C/D LOF mutations were significantly correlated with better outcomes of ICIs therapy in colorectal cancer, suggesting it can be as a useful predictor for response to ICIs in colorectal cancer. Meanwhile, we found the associations of KMT2C/D LOF with the levels of TILs in colorectal cancer, but not in other cancer types, indicating that the efficacy of ICIs was consistent with the levels of TILs.

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Two homologous regulatory genes, lin-12 and glp-1, have overlapping functions

Development ◽

10.1242/dev.112.1.231 ◽

1991 ◽

Vol 112 (1) ◽

pp. 231-240 ◽

Cited By ~ 54

Author(s):

E.J. Lambie ◽

J. Kimble

Keyword(s):

Gene Expression ◽

Double Mutant ◽

Transmembrane Proteins ◽

Cell Interactions ◽

Loss Of Function ◽

Cell Fates ◽

Single Mutant ◽

C Elegans ◽

Homologous Genes ◽

Mutant Phenotypes

Two homologous genes, lin-12 and glp-1, encode transmembrane proteins required for regulatory cell interactions during C. elegans development. Based on their single mutant phenotypes, each gene has been thought to govern a distinct set of cell fates. We show here that lin-12 and glp-1 are functionally redundant during embryogenesis: Unlike either single mutant, the lin-12 glp-1 double mutant dies soon after hatching. Numerous cellular defects can be observed in these Lag (for lin-12 and glp-1) double mutants. Furthermore, we have identified two genes, lag-1 and lag-2, that appear to be required for both lin-12 and glp-1-mediated cell interactions. Strong loss-of-function lag mutants are phenotypically indistinguishable from the lin-12 glp-1 double; weak lag mutants have phenotypes typical of lin-12 and glp-1 single mutants. We speculate that the lin-12 and glp-1 proteins are biochemically interchangeable and that their divergent roles in development may rely largely on differences in gene expression.

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Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma

BMC Cancer ◽

10.1186/s12885-020-07456-2 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Wenshuai Liu ◽

Hanxing Tong ◽

Chenlu Zhang ◽

Rongyuan Zhuang ◽

He Guo ◽

...

Keyword(s):

Gene Expression ◽

Sanger Sequencing ◽

Immune Cell ◽

Gene Copy Number ◽

Gene Copy ◽

Rna Seq ◽

Loss Of Function ◽

Rt Pcr ◽

The Difference ◽

Histologic Types

Abstract Background Treating patients with advanced sarcomas is challenging due to great histologic diversity among its subtypes. Leiomyosarcoma (LMS) and de-differentiated liposarcoma (DDLPS) are two common and aggressive subtypes of soft tissue sarcoma (STS). They differ significantly in histology and clinical behaviors. However, the molecular driving force behind the difference is unclear. Methods We collected 20 LMS and 12 DDLPS samples and performed whole exome sequencing (WES) to obtain their somatic mutation profiles. We also performed RNA-Seq to analyze the transcriptomes of 8 each of the LMS and DDLPS samples and obtained information about differential gene expression, pathway enrichment, immune cell infiltration in tumor microenvironment, and chromosomal rearrangement including gene fusions. Selected gene fusion events from the RNA-seq prediction were checked by RT-PCR in tandem with Sanger sequencing. Results We detected loss of function mutation and deletion of tumor suppressors mostly in LMS, and oncogene amplification mostly in DDLPS. A focal amplification affecting chromosome 12q13–15 region which encodes MDM2, CDK4 and HMGA2 is notable in DDLPS. Mutations in TP53, ATRX, PTEN, and RB1 are identified in LMS but not DDLPS, while mutation of HERC2 is only identified in DDLPS but not LMS. RNA-seq revealed overexpression of MDM2, CDK4 and HMGA2 in DDLPS and down-regulation of TP53 and RB1 in LMS. It also detected more fusion events in DDLPS than LMS (4.5 vs. 1, p = 0.0195), and the ones involving chromosome 12 in DDLPS stand out. RT-PCR and Sanger sequencing verified the majority of the fusion events in DDLPS but only one event in LMS selected to be tested. The tumor microenvironmental signatures are highly correlated with histologic types. DDLPS has more endothelial cells and fibroblasts content than LMS. Conclusions Our analysis revealed different recurrent genetic variations in LMS and DDLPS including simultaneous upregulation of gene expression and gene copy number amplification of MDM2 and CDK4. Up-regulation of tumor related genes is favored in DDLPS, while loss of suppressor function is favored in LMS. DDLPS harbors more frequent fusion events which can generate neoepitopes and potentially targeted by personalized immune treatment.

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The COP9 signalosome influences the epigenetic landscape of Arabidopsis thaliana

Bioinformatics ◽

10.1093/bioinformatics/bty1053 ◽

2018 ◽

Vol 35 (16) ◽

pp. 2718-2723 ◽

Cited By ~ 3

Author(s):

Tamir Tuller ◽

Alon Diament ◽

Avital Yahalom ◽

Assaf Zemach ◽

Shimshi Atar ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Arabidopsis Thaliana ◽

Gene Expression Regulation ◽

Developmental Pathways ◽

Cop9 Signalosome ◽

Supplementary Information ◽

Loss Of Function ◽

Genome Wide ◽

High Level

Abstract Motivation The COP9 signalosome is a highly conserved multi-protein complex consisting of eight subunits, which influences key developmental pathways through its regulation of protein stability and transcription. In Arabidopsis thaliana, mutations in the COP9 signalosome exhibit a number of diverse pleiotropic phenotypes. Total or partial loss of COP9 signalosome function in Arabidopsis leads to misregulation of a number of genes involved in DNA methylation, suggesting that part of the pleiotropic phenotype is due to global effects on DNA methylation. Results We determined and analyzed the methylomes and transcriptomes of both partial- and total-loss-of-function Arabidopsis mutants of the COP9 signalosome. Our results support the hypothesis that the COP9 signalosome has a global genome-wide effect on methylation and that this effect is at least partially encoded in the DNA. Our analyses suggest that COP9 signalosome-dependent methylation is related to gene expression regulation in various ways. Differentially methylated regions tend to be closer in the 3D conformation of the genome to differentially expressed genes. These results suggest that the COP9 signalosome has a more comprehensive effect on gene expression than thought before, and this is partially related to regulation of methylation. The high level of COP9 signalosome conservation among eukaryotes may also suggest that COP9 signalosome regulates methylation not only in plants but also in other eukaryotes, including humans. Supplementary information Supplementary data are available at Bioinformatics online.

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Rapid, high efficiency virus-mediated mutant complementation and gene silencing in Antirrhinum

Plant Methods ◽

10.1186/s13007-020-00683-5 ◽

2020 ◽

Vol 16 (1) ◽

Author(s):

Ying Tan ◽

Alfredas Bukys ◽

Attila Molnár ◽

Andrew Hudson

Keyword(s):

Gene Expression ◽

Gene Silencing ◽

High Efficiency ◽

Tobacco Rattle Virus ◽

Transient Gene Expression ◽

Mutant Phenotype ◽

Homologous Sequence ◽

Homologous Gene ◽

Loss Of Function ◽

H Protein

Abstract Background Antirrhinum (snapdragon) species are models for genetic and evolutionary research but recalcitrant to genetic transformation, limiting use of transgenic methods for functional genomics. Transient gene expression from viral vectors and virus-induced gene silencing (VIGS) offer transformation-free alternatives. Here we investigate the utility of Tobacco rattle virus (TRV) for homologous gene expression in Antirrhinum and VIGS in Antirrhinum and its relative Misopates. Results A. majus proved highly susceptible to systemic TRV infection. TRV carrying part of the Phytoene Desaturase (PDS) gene triggered efficient PDS silencing, visible as tissue bleaching, providing a reporter for the extent and location of VIGS. VIGS was initiated most frequently in young seedlings, persisted into inflorescences and flowers and was not significantly affected by the orientation of the homologous sequence within the TRV genome. Its utility was further demonstrated by reducing expression of two developmental regulators that act either in the protoderm of young leaf primordia or in developing flowers. The effects of co-silencing PDS and the trichome-suppressing Hairy (H) gene from the same TRV genome showed that tissue bleaching provides a useful marker for VIGS of a second target gene acting in a different cell layer. The ability of TRV-encoded H protein to complement the h mutant phenotype was also tested. TRV carrying the native H coding sequence with PDS to report infection failed to complement h mutations and triggered VIGS of H in wild-type plants. However, a sequence with 43% synonymous substitutions encoding H protein, was able to complement the h mutant phenotype when expressed without a PDS VIGS reporter. Conclusions We demonstrate an effective method for VIGS in the model genus Antirrhinum and its relative Misopates that works in vegetative and reproductive tissues. We also show that TRV can be used for complementation of a loss-of-function mutation in Antirrhinum. These methods make rapid tests of gene function possible in these species, which are difficult to transform genetically, and opens up the possibility of using additional cell biological and biochemical techniques that depend on transgene expression.

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