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2023 ◽  
Vol 83 ◽  
Author(s):  
S. U. Rehman ◽  
K. Muhammad ◽  
E. Novaes ◽  
Y. Que ◽  
A. Din ◽  
...  

Abstract Transcription factors (TF) are a wide class of genes in plants, and these can regulate the expression of other genes in response to various environmental stresses (biotic and abiotic). In the current study, transcription factor activity in sugarcane was examined during cold stress. Initially, RNA transcript reads of two sugarcane cultivars (ROC22 and GT08-1108) under cold stress were downloaded from SRA NCBI database. The reads were aligned into a reference genome and the differential expression analyses were performed with the R/Bioconductor edgeR package. Based on our analyses in the ROC22 cultivar, 963 TF genes were significantly upregulated under cold stress among a total of 5649 upregulated genes, while 293 TF genes were downregulated among a total of 3,289 downregulated genes. In the GT08-1108 cultivar, 974 TF genes were identified among 5,649 upregulated genes and 283 TF genes were found among 3,289 downregulated genes. Most transcription factors were annotated with GO categories related to protein binding, transcription factor binding, DNA-sequence-specific binding, transcription factor complex, transcription factor activity in RNA polymerase II, the activity of nucleic acid binding transcription factor, transcription corepressor activity, sequence-specific regulatory region, the activity of transcription factor of RNA polymerase II, transcription factor cofactor activity, transcription factor activity from plastid promoter, transcription factor activity from RNA polymerase I promoter, polymerase II and RNA polymerase III. The findings of above results will help to identify differentially expressed transcription factors during cold stress. It also provides a comprehensive analysis of the regulation of the transcription activity of many genes. Therefore, this study provides the molecular basis for improving cold tolerance in sugarcane and other economically important grasses.


2022 ◽  
Vol 119 (3) ◽  
pp. e2105171119
Author(s):  
Raghuvaran Shanmugam ◽  
Mert Burak Ozturk ◽  
Joo-Leng Low ◽  
Semih Can Akincilar ◽  
Joelle Yi Heng Chua ◽  
...  

Cancer-specific hTERT promoter mutations reported in 19% of cancers result in enhanced telomerase activity. Understanding the distinctions between transcriptional regulation of wild-type (WT) and mutant (Mut) hTERT promoters may open up avenues for development of inhibitors which specially block hTERT expression in cancer cells. To comprehensively identify physiological regulators of WT- or Mut-hTERT promoters, we generated several isogenic reporter cells driven by endogenous hTERT loci. Genome-wide CRISPR-Cas9 and small interfering RNA screens using these isogenic reporter lines identified specific regulators of Mut-hTERT promoters. We validate and characterize one of these hits, namely, MED12, a kinase subunit of mediator complex. We demonstrate that MED12 specifically drives expression of hTERT from the Mut-hTERT promoter by mediating long-range chromatin interaction between the proximal Mut-hTERT promoter and T-INT1 distal regulatory region 260 kb upstream. Several hits identified in our screens could serve as potential therapeutic targets, inhibition of which may specifically block Mut-hTERT promoter driven telomerase reactivation in cancers.


2022 ◽  
Vol 12 ◽  
Author(s):  
A. I. Chekunova ◽  
S. Yu. Sorokina ◽  
E. A. Sivoplyas ◽  
G. N. Bakhtoyarov ◽  
P. A. Proshakov ◽  
...  

As assemblies of genomes of new species with varying degrees of relationship appear, it becomes obvious that structural rearrangements of the genome, such as inversions, translocations, and transposon movements, are an essential and often the main source of evolutionary variation. In this regard, the following questions arise. How conserved are the regulatory regions of genes? Do they have a common evolutionary origin? And how and at what rate is the functional activity of genes restored during structural changes in the promoter region? In this article, we analyze the evolutionary history of the formation of the regulatory region of the ras85D gene in different lineages of the genus Drosophila, as well as the participation of mobile elements in structural rearrangements and in the replacement of specific areas of the promoter region with those of independent evolutionary origin. In the process, we substantiate hypotheses about the selection of promoter elements from a number of frequently repeated motifs with different degrees of degeneracy in the ancestral sequence, as well as about the restoration of the minimum required set of regulatory sequences using a conversion mechanism or similar.


2022 ◽  
Author(s):  
Jing You ◽  
Wenwen Xiao ◽  
Yue Zhou ◽  
Li Ye ◽  
Guoling Yu ◽  
...  

Leaf morphology is one of the most important features of the ideal plant architecture. However, the genetic and molecular mechanisms controlling leaf morphology in crops remain largely unknown, despite their central importance. Here we demonstrate that the APC/CTAD1-WL1-NAL1 pathway regulates leaf width in rice, and mutation of WL1 leads to width leaf variation. WL1 interacts with TAD1 and is degraded by APC/CTAD1, with the loss of TAD1 function resulting in narrow leaves. The WL1 protein directly binds to the regulatory region of NAL1 and recruits the corepressor TOPLESS-RELATED PROTEIN to inhibit NAL1 expression by down-regulating the level of histone acetylation of chromatin. Furthermore, biochemical and genetic analyses revealed that TAD1, WL1, and NAL1 function in a common pathway to control leaf width. Our study establishes an important framework for the APC/CTAD1-WL1-NAL1 pathway-mediated control of leaf width in rice and introduces novel perspectives for using this regulatory pathway for improving crop plant architecture.


2022 ◽  
Vol 18 (1) ◽  
pp. e1010149
Author(s):  
Evan John ◽  
Silke Jacques ◽  
Huyen T. T. Phan ◽  
Lifang Liu ◽  
Danilo Pereira ◽  
...  

The fungus Parastagonospora nodorum uses proteinaceous necrotrophic effectors (NEs) to induce tissue necrosis on wheat leaves during infection, leading to the symptoms of septoria nodorum blotch (SNB). The NEs Tox1 and Tox3 induce necrosis on wheat possessing the dominant susceptibility genes Snn1 and Snn3B1/Snn3D1, respectively. We previously observed that Tox1 is epistatic to the expression of Tox3 and a quantitative trait locus (QTL) on chromosome 2A that contributes to SNB resistance/susceptibility. The expression of Tox1 is significantly higher in the Australian strain SN15 compared to the American strain SN4. Inspection of the Tox1 promoter region revealed a 401 bp promoter genetic element in SN4 positioned 267 bp upstream of the start codon that is absent in SN15, called PE401. Analysis of the world-wide P. nodorum population revealed that a high proportion of Northern Hemisphere isolates possess PE401 whereas the opposite was observed in representative P. nodorum isolates from Australia and South Africa. The presence of PE401 removed the epistatic effect of Tox1 on the contribution of the SNB 2A QTL but not Tox3. PE401 was introduced into the Tox1 promoter regulatory region in SN15 to test for direct regulatory roles. Tox1 expression was markedly reduced in the presence of PE401. This suggests a repressor molecule(s) binds PE401 and inhibits Tox1 transcription. Infection assays also demonstrated that P. nodorum which lacks PE401 is more pathogenic on Snn1 wheat varieties than P. nodorum carrying PE401. An infection competition assay between P. nodorum isogenic strains with and without PE401 indicated that the higher Tox1-expressing strain rescued the reduced virulence of the lower Tox1-expressing strain on Snn1 wheat. Our study demonstrated that Tox1 exhibits both ‘selfish’ and ‘altruistic’ characteristics. This offers an insight into a complex NE-NE interaction that is occurring within the P. nodorum population. The importance of PE401 in breeding for SNB resistance in wheat is discussed.


PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0254466
Author(s):  
Ting-Yun Chen ◽  
Xiaoyun Li ◽  
Gillian C. Goobie ◽  
Ching-Hsia Hung ◽  
Tin-Kan Hung ◽  
...  

Relaxin/insulin-like family peptide receptor 1 (RXFP1) mediates relaxin’s antifibrotic effects and has reduced expression in the lung and skin of patients with fibrotic interstitial lung disease (fILD) including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). This may explain the failure of relaxin-based anti-fibrotic treatments in SSc, but the regulatory mechanisms controlling RXFP1 expression remain largely unknown. This study aimed to identify regulatory elements of RXFP1 that may function differentially in fibrotic fibroblasts. We identified and evaluated a distal regulatory region of RXFP1 in lung fibroblasts using a luciferase reporter system. Using serial deletions, an enhancer upregulating pGL3-promoter activity was localized to the distal region between -584 to -242bp from the distal transcription start site (TSS). This enhancer exhibited reduced activity in IPF and SSc lung fibroblasts. Bioinformatic analysis identified two clusters of activator protein 1 (AP-1) transcription factor binding sites within the enhancer. Site-directed mutagenesis of the binding sites confirmed that only one cluster reduced activity (-358 to -353 relative to distal TSS). Co-expression of FOS in lung fibroblasts further increased enhancer activity. In vitro complex formation with a labeled probe spanning the functional AP-1 site using nuclear proteins isolated from lung fibroblasts confirmed a specific DNA/protein complex formation. Application of antibodies against JUN and FOS resulted in the complex alteration, while antibodies to JUNB and FOSL1 did not. Analysis of AP-1 binding in 5 pairs of control and IPF lung fibroblasts detected positive binding more frequently in control fibroblasts. Expression of JUN and FOS was reduced and correlated positively with RXFP1 expression in IPF lungs. In conclusion, we identified a distal enhancer of RXFP1 with differential activity in fibrotic lung fibroblasts involving AP-1 transcription factors. Our study provides insight into RXFP1 downregulation in fILD and may support efforts to reevaluate relaxin-based therapeutics alongside upregulation of RXFP1 transcription.


Antibiotics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 29
Author(s):  
Joseph Yamweka Chizimu ◽  
Eddie Samuneti Solo ◽  
Precious Bwalya ◽  
Wimonrat Tanomsridachchai ◽  
Herman Chambaro ◽  
...  

Globally, tuberculosis (TB) is a major cause of death due to antimicrobial resistance. Mycobacterium tuberculosis CAS1-Kili strains that belong to lineage 3 (Central Asian Strain, CAS) were previously implicated in the spread of multidrug-resistant (MDR)-TB in Lusaka, Zambia. Thus, we investigated recent transmission of those strains by whole-genome sequencing (WGS) with Illumina MiSeq platform. Twelve MDR CAS1-Kili isolates clustered by traditional methods (MIRU-VNTR and spoligotyping) were used. A total of 92% (11/12) of isolates belonged to a cluster (≤12 SNPs) while 50% (6/12) were involved in recent transmission events, as they differed by ≤5 SNPs. All the isolates had KatG Ser315Thr (isoniazid resistance), EmbB Met306 substitutions (ethambutol resistance) and several kinds of rpoB mutations (rifampicin resistance). WGS also revealed compensatory mutations including a novel deletion in embA regulatory region (−35A > del). Several strains shared the same combinations of drug-resistance-associated mutations indicating transmission of MDR strains. Zambian strains belonged to the same clade as Tanzanian, Malawian and European strains, although most of those were pan-drug-susceptible. Hence, complimentary use of WGS to traditional epidemiological methods provides an in-depth insight on transmission and drug resistance patterns which can guide targeted control measures to stop the spread of MDR-TB.


2021 ◽  
Author(s):  
Tyler Hansen ◽  
Emily Hodges

Transcriptional enhancers control cell-type specific gene expression in humans and dysfunction can lead to debilitating diseases, including cancer. Identifying bona-fide enhancers is difficult due to a lack of spatial or sequence constraints. In addition, only a small percentage of the genome is accessible in matured cell types; and therefore, most enhancers are inactive due to their chromatin context rather than intrinsic properties of the DNA sequence itself. For this reason, we decided to assay regulatory activity exclusively within accessible chromatin. To do this, we combined assay for transposase-accessible chromatin using sequencing (ATAC-seq) with self-transcribing active regulatory region sequencing (STARR-seq); we call this method ATAC-STARR-seq. With ATAC-STARR-seq, we identify both active and silent regulatory elements in GM12878 B cells; these active and silent elements are enriched for transcription factor motifs and histone modifications associated with activating and repressing regulation, respectively. We also show that ATAC-STARR-seq quantifies chromatin accessibility and transcription factor binding. We integrate this information and subset active regions based on transcription factor binding profiles. Depending on the transcription factors bound, subsets are enriched for distinct reactome pathways. Altogether, this highlights the power of ATAC-STARR-seq to investigate the transcriptional regulatory landscape of the human genome.


2021 ◽  
Author(s):  
Tyler Hansen ◽  
Emily Hodges

Massively parallel reporter assays test the capacity of putative cis-regulatory elements (CREs) to drive transcription on a genome-wide scale. In nearly all cases, chromatin accessibility is necessary to drive activity, so most CREs are inactive due to chromatin context rather than intrinsic DNA sequence properties. Here, we combined assay for transposase-accessible chromatin (ATAC-seq) with self-transcribing active regulatory region sequencing (STARR-seq) to selectively assay the regulatory potential of nucleosome-free DNA genome-wide. Our approach enabled high-resolution testing of ~50 million unique DNA fragments tiling ~101,000 accessible chromatin regions in human lymphoblastoid cells. To illustrate the application of our approach, we show that 30% of all accessible regions contain an activator, a silencer or both. Benchmarking against standard ATAC-seq, our approach faithfully captures chromatin accessibility and transcription factor (TF) footprints with high signal-to-noise. Integrating three layers of genomic information (accessibility, TF occupancy, and activity) provided by ATAC-STARR-seq, we stratified active and silent CREs by the presence of several TF footprints and show that CREs with specific TF combinations are associated with distinct gene regulatory pathways. Altogether, these data highlight the power of ATAC-STARR-seq to comprehensively investigate the regulatory landscape of the human genome from a single DNA source.


2021 ◽  
Author(s):  
Matthew N. Wakeling ◽  
Nick D. L. Owens ◽  
Jessica R. Hopkinson ◽  
Matthew B. Johnson ◽  
Jayne A.L. Houghton ◽  
...  

AbstractGene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function. This silencing is largely controlled by non-coding elements and their disruption might cause human disease. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo mutations affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1), a pancreatic beta-cell disallowed gene. We demonstrated that these mutations resulted in expression of HK1 in the pancreatic beta-cells causing inappropriate insulin secretion and congenital hyperinsulinism. These mutations identify a regulatory region critical for cell-specific silencing. Importantly, this has revealed a new disease mechanism for non-coding mutations that cause inappropriate expression of a disallowed gene.


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