Combinatorial control of diverse metabolic and physiological functions by transcriptional regulators of the yeast sulfur assimilation pathway

Methionine abundance affects diverse cellular functions, including cell division, redox homeostasis, survival under starvation, and oxidative stress response. Regulation of the methionine biosynthetic pathway involves three DNA-binding proteins—Met31p, Met32p, and Cbf1p. We hypothesized that there exists a “division of labor” among these proteins that facilitates coordination of methionine biosynthesis with diverse biological processes. To explore combinatorial control in this regulatory circuit, we deleted CBF1, MET31, and MET32 individually and in combination in a strain lacking methionine synthase. We followed genome-wide gene expression as these strains were starved for methionine. Using a combination of bioinformatic methods, we found that these regulators control genes involved in biological processes downstream of sulfur assimilation; many of these processes had not previously been documented as methionine dependent. We also found that the different factors have overlapping but distinct functions. In particular, Met31p and Met32p are important in regulating methionine metabolism, whereas Cbf1p functions as a “generalist” transcription factor that is not specific to methionine metabolism. In addition, Met31p and Met32p appear to regulate iron–sulfur cluster biogenesis through direct and indirect mechanisms and have distinguishable target specificities. Finally, CBF1 deletion sometimes has the opposite effect on gene expression from MET31 and MET32 deletion.

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Increased Expression of CCN2 in the Red Flashing Light-Induced Myopia in Guinea Pigs

BioMed Research International ◽

10.1155/2013/761823 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Hong Wang ◽

Kang Zhuang ◽

Lei Gao ◽

Linna Zhang ◽

Hongling Yang

Keyword(s):

Gene Expression ◽

Animal Model ◽

Axial Length ◽

Growth And Development ◽

Visual Environment ◽

Biological Processes ◽

Cellular Functions ◽

Ocular Growth ◽

Flashing Light

Visual environment plays an important role in the occurrence of myopia. We previously showed that the different flashing lights could result in distinct effects on the ocular growth and development of myopia. CCN2 has been reported to regulate various cellular functions and biological processes. However, whether CCN2 signaling was involved in the red flashing light-induced myopia still remains unknown. In the present study, we investigated the effects of the red flashing lights exposure on the refraction and axial length of the eyesin vivoand then evaluated their effects on the expression of CCN2 and TGF-βin sclera tissues. Our data showed that the eyes exposed to the red flashing light became more myopic with a significant increase of the axial length and decrease of the refraction. Both CCN2 and TGF-β, as well as p38 MAPK and PI3K, were highly expressed in the sclera tissues exposed to the red flashing light. Both CCN2 and TGF-βwere found to have the same gene expression profilein vivo. In conclusion, our findings found that CCN2 signaling pathway plays an important role in the red flashing light-induced myopiain vivo. Moreover, our study establishes a useful animal model for experimental myopia research.

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Integrated analysis of transcriptome and histone modifications in granulosa cells during ovulation in female mice

Endocrinology ◽

10.1210/endocr/bqab128 ◽

2021 ◽

Author(s):

Yuichiro Shirafuta ◽

Isao Tamura ◽

Yasuyuki Ohkawa ◽

Ryo Maekawa ◽

Yumiko Doi-Tanaka ◽

...

Keyword(s):

Gene Expression ◽

Immune System ◽

Inflammatory Response ◽

Histone Modifications ◽

Granulosa Cells ◽

Cellular Functions ◽

Lh Surge ◽

Genome Wide ◽

Ros Metabolism ◽

Rapid Changes

Abstract The ovulatory luteinizing hormone (LH) surge induces rapid changes of gene expression and cellular functions in granulosa cells (GCs) undergoing luteinization. However, it remains unclear how the changes in genome-wide gene expression are regulated. H3K4me3 histone modifications are involved in rapid alteration of gene expression. In this study, we investigated genome-wide changes of transcriptome and H3K4me3 status in mouse GCs undergoing luteinization. GCs were obtained from mice treated with equine chorionic gonadotropin (eCG) before, 4 h and 12 h after human (h)CG injection. RNA-sequencing identified a number of up- and down-regulated genes, which could be classified into eight patterns according to the time-course changes of gene expression. Many genes were transiently up- or down-regulated at 4 h after hCG stimulation. Gene ontology terms associated with these genes included steroidogenesis, ovulation, COC expansion, angiogenesis, immune system, ROS metabolism, inflammatory response, metabolism and autophagy. The cellular functions of DNA repair and cell growth were newly identified as being activated during ovulation. ChIP-sequencing revealed a genome-wide and rapid change of H3K4me3 during ovulation. Integration of transcriptome and H3K4me3 data identified many H3K4me3-associated genes that are involved in steroidogenesis, ovulation, COC expansion, angiogenesis, inflammatory response, immune system, ROS metabolism, lipid and glucose metabolism, autophagy, and regulation of cell size. The present results suggest that genome-wide changes in H3K4me3 after the LH surge are associated with rapid changes in gene expression in GCs, which enables GCs acquire a lot of cellular functions within a short time that are required for ovulation and luteinization.

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Sex-chromosome dosage effects on gene expression in humans

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802889115 ◽

2018 ◽

Vol 115 (28) ◽

pp. 7398-7403 ◽

Cited By ~ 46

Author(s):

Armin Raznahan ◽

Neelroop N. Parikshak ◽

Vijay Chandran ◽

Jonathan D. Blumenthal ◽

Liv S. Clasen ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Sex Chromosome ◽

Theoretical Models ◽

Cellular Functions ◽

Systematic Map ◽

Genome Expression ◽

Dosage Effects ◽

Genome Wide ◽

Coexpression Networks

A fundamental question in the biology of sex differences has eluded direct study in humans: How does sex-chromosome dosage (SCD) shape genome function? To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse sex-chromosome aneuploidies (XO, XXX, XXY, XYY, and XXYY). For sex chromosomes, we demonstrate a pattern of obligate dosage sensitivity among evolutionarily preserved X-Y homologs and update prevailing theoretical models for SCD compensation by detecting X-linked genes that increase expression with decreasing X- and/or Y-chromosome dosage. We further show that SCD-sensitive sex-chromosome genes regulate specific coexpression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. These gene coexpression results converge with analysis of transcription factor binding site enrichment and measures of gene expression in murine knockout models to spotlight the dosage-sensitive X-linked transcription factor ZFX as a key mediator of SCD effects on wider genome expression. Our findings characterize the effects of SCD broadly across the genome, with potential implications for human phenotypic variation.

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Impact of Gene Dosage on Gene Expression, Biological Processes and Survival in Cervical Cancer: A Genome-Wide Follow-Up Study

PLoS ONE ◽

10.1371/journal.pone.0097842 ◽

2014 ◽

Vol 9 (5) ◽

pp. e97842 ◽

Cited By ~ 18

Author(s):

Ingrid Medina-Martinez ◽

Valeria Barrón ◽

Edgar Roman-Bassaure ◽

Eligia Juárez-Torres ◽

Mariano Guardado-Estrada ◽

...

Keyword(s):

Gene Expression ◽

Cervical Cancer ◽

Gene Dosage ◽

Biological Processes ◽

Follow Up Study ◽

Genome Wide ◽

A Genome

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Perturbation-based analysis and modeling of combinatorial regulation in the yeast sulfur assimilation pathway

Molecular Biology of the Cell ◽

10.1091/mbc.e12-03-0232 ◽

2012 ◽

Vol 23 (15) ◽

pp. 2993-3007 ◽

Cited By ~ 30

Author(s):

R. Scott McIsaac ◽

Allegra A. Petti ◽

Harmen J. Bussemaker ◽

David Botstein

Keyword(s):

Ubiquitin Ligase ◽

Binding Sites ◽

Regulatory System ◽

Methionine Biosynthesis ◽

Sulfur Assimilation ◽

Combinatorial Regulation ◽

Physiological Conditions ◽

Genome Wide ◽

Combinatorial Control ◽

State Growth

In yeast, the pathways of sulfur assimilation are combinatorially controlled by five transcriptional regulators (three DNA-binding proteins [Met31p, Met32p, and Cbf1p], an activator [Met4p], and a cofactor [Met28p]) and a ubiquitin ligase subunit (Met30p). This regulatory system exerts combinatorial control not only over sulfur assimilation and methionine biosynthesis, but also on many other physiological functions in the cell. Recently we characterized a gene induction system that, upon the addition of an inducer, results in near-immediate transcription of a gene of interest under physiological conditions. We used this to perturb levels of single transcription factors during steady-state growth in chemostats, which facilitated distinction of direct from indirect effects of individual factors dynamically through quantification of the subsequent changes in genome-wide patterns of gene expression. We were able to show directly that Cbf1p acts sometimes as a repressor and sometimes as an activator. We also found circumstances in which Met31p/Met32p function as repressors, as well as those in which they function as activators. We elucidated and numerically modeled feedback relationships among the regulators, notably feedforward regulation of Met32p (but not Met31p) by Met4p that generates dynamic differences in abundance that can account for the differences in function of these two proteins despite their identical binding sites.

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Coordinated genomic control of ciliogenesis and cell movement by RFX2

eLife ◽

10.7554/elife.01439 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 73

Author(s):

Mei-I Chung ◽

Taejoon Kwon ◽

Fan Tu ◽

Eric R Brooks ◽

Rakhi Gupta ◽

...

Keyword(s):

Gene Expression ◽

Control Cell ◽

Cell Movement ◽

Genomic Analysis ◽

Apical Surface ◽

Biological Processes ◽

Cellular Functions ◽

Genomic Control ◽

And Function

The mechanisms linking systems-level programs of gene expression to discrete cell biological processes in vivo remain poorly understood. In this study, we have defined such a program for multi-ciliated epithelial cells (MCCs), a cell type critical for proper development and homeostasis of the airway, brain and reproductive tracts. Starting from genomic analysis of the cilia-associated transcription factor Rfx2, we used bioinformatics and in vivo cell biological approaches to gain insights into the molecular basis of cilia assembly and function. Moreover, we discovered a previously un-recognized role for an Rfx factor in cell movement, finding that Rfx2 cell-autonomously controls apical surface expansion in nascent MCCs. Thus, Rfx2 coordinates multiple, distinct gene expression programs in MCCs, regulating genes that control cell movement, ciliogenesis, and cilia function. As such, the work serves as a paradigm for understanding genomic control of cell biological processes that span from early cell morphogenetic events to terminally differentiated cellular functions.

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Inheritance of gene expression throughout fruit development in chili pepper

Scientific Reports ◽

10.1038/s41598-021-02151-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Christian Escoto-Sandoval ◽

Neftalí Ochoa-Alejo ◽

Octavio Martínez

Keyword(s):

Gene Expression ◽

Fruit Development ◽

Gene Expression Regulation ◽

R Package ◽

Chili Pepper ◽

Wild Accession ◽

Biological Processes ◽

Genome Wide ◽

Cell Components

AbstractGene expression is the primary molecular phenotype and can be estimated in specific organs or tissues at particular times. Here we analyzed genome-wide inheritance of gene expression in fruits of chili pepper (Capsicum annuum L.) in reciprocal crosses between a domesticated and a wild accession, estimating this parameter during fruit development. We defined a general hierarchical schema to classify gene expression inheritance which can be employed for any quantitative trait. We found that inheritance of gene expression is affected by both, the time of fruit development as well as the direction of the cross, and propose that such variations could be common in many developmental processes. We conclude that classification of inheritance patterns is important to have a better understanding of the mechanisms underlying gene expression regulation, and demonstrate that sets of genes with specific inheritance pattern at particular times of fruit development are enriched in different biological processes, molecular functions and cell components. All curated data and functions for analysis and visualization are publicly available as an R package.

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Introduction to GRNs

Handbook of Research on Computational Methodologies in Gene Regulatory Networks ◽

10.4018/978-1-60566-685-3.ch002 ◽

2010 ◽

pp. 28-56

Author(s):

Ugo Ala ◽

Christian Damasco

Keyword(s):

Gene Expression ◽

High Throughput ◽

System Biology ◽

Regulatory Networks ◽

New Technologies ◽

Single Gene ◽

Biological Processes ◽

Genome Wide ◽

Genes Expression ◽

Organization Analysis

The post-genomic era shifted the main biological focus from ‘single-gene’ to ‘genome-wide’ approaches. High throughput data available from new technologies allowed to get inside main features of gene expression and its regulation and, at the same time, to discover a more complex level of organization. Analysis of this complexity demonstrated the existence of nonrandom and well-defined structures that determine a network of interactions. In the first part of the chapter, we present a functional introduction to mechanisms involved in genes expression regulation, an overview of network theory, and main technologies developed in recent years to analyze biological processes are discussed. In the second part, we review genes regulatory networks and their importance in system biology.

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