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1. The cis-regulatory codes of response to combined heat and drought stress in Arabidopsis thaliana

   https://doi.org/10.1093/nargab/lqaa049  

   Azodi, Christina B; Lloyd, John P; Shiu, Shin-Han (September 2020, NAR Genomics and Bioinformatics)

   null (Ed.)

   Abstract Plants respond to their environment by dynamically modulating gene expression. A powerful approach for understanding how these responses are regulated is to integrate information about cis-regulatory elements (CREs) into models called cis-regulatory codes. Transcriptional response to combined stress is typically not the sum of the responses to the individual stresses. However, cis-regulatory codes underlying combined stress response have not been established. Here we modeled transcriptional response to single and combined heat and drought stress in Arabidopsis thaliana. We grouped genes by their pattern of response (independent, antagonistic and synergistic) and trained machine learning models to predict their response using putative CREs (pCREs) as features (median F-measure = 0.64). We then developed a deep learning approach to integrate additional omics information (sequence conservation, chromatin accessibility and histone modification) into our models, improving performance by 6.2%. While pCREs important for predicting independent and antagonistic responses tended to resemble binding motifs of transcription factors associated with heat and/or drought stress, important synergistic pCREs resembled binding motifs of transcription factors not known to be associated with stress. These findings demonstrate how in silico approaches can improve our understanding of the complex codes regulating response to combined stress and help us identify prime targets for future characterization. 

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2. A Novel cis Element Achieves the Same Solution as an Ancestral cis Element During Thiamine Starvation in Candida glabrata

   https://doi.org/10.1534/g3.119.400897  

   Iosue, Christine L.; Gulotta, Anthony P.; Selhorst, Kathleen B.; Mody, Alison C.; Barbour, Kristin M.; Marcotte, Meredith J.; Bui, Lilian N.; Leone, Sarah G.; Lang, Emma C.; Hughes, Genevieve H.; et al (January 2020, G3: Genes|Genomes|Genetics)

   Regulatory networks often converge on very similar cis sequences to drive transcriptional programs due to constraints on what transcription factors are present. To determine the role of constraint loss on cis element evolution, we examined the recent appearance of a thiamine starvation regulated promoter in Candida glabrata . This species lacks the ancestral transcription factor Thi2, but still has the transcription factor Pdc2, which regulates thiamine starvation genes, allowing us to determine the effect of constraint change on a new promoter. We identified two different cis elements in C. glabrata - one present in the evolutionarily recent gene called CgPMU3 , and the other element present in the other thiamine (THI) regulated genes. Reciprocal swaps of the cis elements and incorporation of the S. cerevisiae Thi2 transcription factor-binding site into these promoters demonstrate that the two elements are functionally different from one another. Thus, this loss of an imposed constraint on promoter function has generated a novel cis sequence, suggesting that loss of trans constraints can generate a non-convergent pathway with the same output. 

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3. Prediction of conserved and variable heat and cold stress response in maize using cis-regulatory information

   https://doi.org/10.1093/plcell/koab267  

   Zhou, Peng; Enders, Tara A; Myers, Zachary A; Magnusson, Erika; Crisp, Peter A; Noshay, Jaclyn M; Gomez-Cano, Fabio; Liang, Zhikai; Grotewold, Erich; Greenham, Kathleen; et al (November 2021, The Plant Cell)

   Abstract Changes in gene expression are important for responses to abiotic stress. Transcriptome profiling of heat- or cold-stressed maize genotypes identifies many changes in transcript abundance. We used comparisons of expression responses in multiple genotypes to identify alleles with variable responses to heat or cold stress and to distinguish examples of cis- or trans-regulatory variation for stress-responsive expression changes. We used motifs enriched near the transcription start sites (TSSs) for thermal stress-responsive genes to develop predictive models of gene expression responses. Prediction accuracies can be improved by focusing only on motifs within unmethylated regions near the TSS and vary for genes with different dynamic responses to stress. Models trained on expression responses in a single genotype and promoter sequences provided lower performance when applied to other genotypes but this could be improved by using models trained on data from all three genotypes tested. The analysis of genes with cis-regulatory variation provides evidence for structural variants that result in presence/absence of transcription factor binding sites in creating variable responses. This study provides insights into cis-regulatory motifs for heat- and cold-responsive gene expression and defines a framework for developing models to predict expression responses across multiple genotypes. 

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4. Evolution of a cis -Acting SNP That Controls Type VI Secretion in Vibrio cholerae

   https://doi.org/10.1128/mbio.00422-22  

   Ng, Siu Lung; Kammann, Sophia; Steinbach, Gabi; Hoffmann, Tobias; Yunker, Peter J.; Hammer, Brian K. (May 2022, mBio)

   Storz, Gisela (Ed.)

   ABSTRACT Mutations in regulatory mechanisms that control gene expression contribute to phenotypic diversity and thus facilitate the adaptation of microbes and other organisms to new niches. Comparative genomics can be used to infer rewiring of regulatory architecture based on large effect mutations like loss or acquisition of transcription factors but may be insufficient to identify small changes in noncoding, intergenic DNA sequence of regulatory elements that drive phenotypic divergence. In human-derived Vibrio cholerae , the response to distinct chemical cues triggers production of multiple transcription factors that can regulate the type VI secretion system (T6), a broadly distributed weapon for interbacterial competition. However, to date, the signaling network remains poorly understood because no regulatory element has been identified for the major T6 locus. Here we identify a conserved cis -acting single nucleotide polymorphism (SNP) controlling T6 transcription and activity. Sequence alignment of the T6 regulatory region from diverse V. cholerae strains revealed conservation of the SNP that we rewired to interconvert V. cholerae T6 activity between chitin-inducible and constitutive states. This study supports a model of pathogen evolution through a noncoding cis -regulatory mutation and preexisting, active transcription factors that confers a different fitness advantage to tightly regulated strains inside a human host and unfettered strains adapted to environmental niches. IMPORTANCE Organisms sense external cues with regulatory circuits that trigger the production of transcription factors, which bind specific DNA sequences at promoters (“ cis ” regulatory elements) to activate target genes. Mutations of transcription factors or their regulatory elements create phenotypic diversity, allowing exploitation of new niches. Waterborne pathogen Vibrio cholerae encodes the type VI secretion system “nanoweapon” to kill competitor cells when activated. Despite identification of several transcription factors, no regulatory element has been identified in the promoter of the major type VI locus, to date. Combining phenotypic, genetic, and genomic analysis of diverse V. cholerae strains, we discovered a single nucleotide polymorphism in the type VI promoter that switches its killing activity between a constitutive state beneficial outside hosts and an inducible state for constraint in a host. Our results support a role for noncoding DNA in adaptation of this pathogen. 

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5. Arabidopsis   PROTODERMAL FACTOR2 binds lysophosphatidylcholines and transcriptionally regulates phospholipid metabolism

   https://doi.org/10.1111/nph.19917  

   Wojciechowska, Izabela; Mukherjee, Thiya; Knox‐Brown, Patrick; Hu, Xueyun; Khosla, Aashima; Subedi, Bibek; Ahmad, Bilal; Mathews, Graham L; Panagakis, Ashley A; Thompson, Kyle A; et al (July 2024, New Phytologist)

   Summary Plant homeodomain leucine zipper IV (HD‐Zip IV) transcription factors (TFs) contain an evolutionarily conserved steroidogenic acute regulatory protein (StAR)‐related lipid transfer (START) domain. While the START domain is required for TF activity, its presumed role as a lipid sensor is not clear.Here we used tandem affinity purification fromArabidopsiscell cultures to demonstrate that PROTODERMAL FACTOR2 (PDF2), a representative member that controls epidermal differentiation, recruits lysophosphatidylcholines (LysoPCs) in a START‐dependent manner. Microscale thermophoresis assays confirmed that a missense mutation in a predicted ligand contact site reduces lysophospholipid binding.We additionally found that PDF2 acts as a transcriptional regulator of phospholipid‐ and phosphate (Pi) starvation‐related genes and binds to a palindromic octamer with consensus to a Pi response element. Phospholipid homeostasis and elongation growth were altered inpdf2mutants according to Pi availability. Cycloheximide chase experiments revealed a role for START in maintaining protein levels, and Pi starvation resulted in enhanced protein destabilization, suggesting a mechanism by which lipid binding controls TF activity.We propose that the START domain serves as a molecular sensor for membrane phospholipid status in the epidermis. Our data provide insights toward understanding how the lipid metabolome integrates Pi availability with gene expression. 

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