scholarly journals The RNA binding protein CPEB2 regulates hormone sensing in mammary gland development and luminal breast cancer

2020 ◽  
Vol 6 (20) ◽  
pp. eaax3868 ◽  
Author(s):  
Rosa Pascual ◽  
Judit Martín ◽  
Fernando Salvador ◽  
Oscar Reina ◽  
Veronica Chanes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mammary Gland ◽  
Mammary Gland Development ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Mrna Translation ◽  
Regulatory Elements ◽  
Expression Regulation ◽  
Luminal Breast Cancer ◽  
Gland Development

Organogenesis is directed by coordinated cell proliferation and differentiation programs. The hierarchical networks of transcription factors driving mammary gland development and function have been widely studied. However, the contribution of posttranscriptional gene expression reprogramming remains largely unexplored. The 3′ untranslated regions of messenger RNAs (mRNAs) contain combinatorial ensembles of cis-regulatory elements that define transcript-specific regulation of protein synthesis through their cognate RNA binding proteins. We analyze the contribution of the RNA binding cytoplasmic polyadenylation element–binding (CPEB) protein family, which collectively regulate mRNA translation for about 30% of the genome. We find that CPEB2 is required for the integration of hormonal signaling by controlling the protein expression from a subset of ER/PR- regulated transcripts. Furthermore, CPEB2 is critical for the development of ER-positive breast tumors. This work uncovers a previously unknown gene expression regulation level in breast morphogenesis and tumorigenesis, coordinating sequential transcriptional and posttranscriptional layers of gene expression regulation.

scholarly journals Actively translated uORFs reduce translation and mRNA stability independent of NMD in Arabidopsis

2021 ◽  
Author(s):  
Hsin-Yen Larry Wu ◽  
Polly Yingshan Hsu
Keyword(s):  
Gene Expression ◽  
Mrna Stability ◽  
Gene Expression Regulation ◽  
Regulatory Elements ◽  
Expression Regulation ◽  
Ribosome Profiling ◽  
Translation Efficiency ◽  
Nonsense Mediated Decay ◽  
Protein Levels ◽  
Eukaryotic Genes

ABSTRACTUpstream ORFs (uORFs) are widespread cis-regulatory elements in the 5’ untranslated regions of eukaryotic genes. Translation of uORFs could negatively regulate protein synthesis by repressing main ORF (mORF) translation and by reducing mRNA stability presumably through nonsense-mediated decay (NMD). While the above expectations were supported in animals, they have not been extensively tested in plants. Using ribosome profiling, we systematically identified 2093 Actively Translated uORFs (ATuORFs) in Arabidopsis seedlings and examined their roles in gene expression regulation by integrating multiple genome-wide datasets. Compared with genes without uORFs, we found ATuORFs result in 38%, 14%, and 43% reductions in translation efficiency, mRNA stability, and protein levels, respectively. The effects of predicted but not actively translated uORFs are much weaker than those of ATuORFs. Interestingly, ATuORF-containing genes are also expressed at higher levels and encode longer proteins with conserved domains, features that are common in evolutionarily older genes. Moreover, we provide evidence that uORF translation in plants, unlike in vertebrates, generally does not trigger NMD. We found ATuORF-containing transcripts are degraded through 5’ to 3’ decay, while NMD targets are degraded through both 5’ to 3’ and 3’ to 5’ decay, suggesting uORF-associated mRNA decay and NMD have distinct genetic requirements. Furthermore, we showed ATuORFs and NMD repress translation through separate mechanisms. Our results reveal that the potent inhibition of uORFs on mORF translation and mRNA stability in plants are independent of NMD, highlighting a fundamental difference in gene expression regulation by uORFs in the plant and animal kingdoms.

scholarly journals Alteration of Mammary Gland Development and Gene Expression by In Utero Exposure to Cadmium

2017 ◽  
Vol 18 (9) ◽  
pp. 1939 ◽  
Author(s):  
Daniela Parodi ◽  
Morgan Greenfield ◽  
Claire Evans ◽  
Anna Chichura ◽  
Alexandra Alpaugh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mammary Gland ◽  
Mammary Gland Development ◽  
In Utero ◽  
In Utero Exposure ◽  
Gland Development

Mammary Epithelial Cell Transcriptome Reveals Potential Roles of lncRNAs in Regulating Milk Synthesis Pathways in Jersey and Kashmiri Cattle

2021 ◽  
Author(s):  
Peerzada Tajamul Mumtaz ◽  
Basharat Bhat ◽  
Eveline M. Ibeagha-Awemu ◽  
Qamar Taban ◽  
Mengqi Wang ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Expression Profiles ◽  
Regulatory Elements ◽  
Milk Quality ◽  
Mammary Epithelial ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Gland Development

Abstract Background Long noncoding RNAs (lncRNAs) are now proven as essential regulatory elements, playing diverse role in many biological processes including mammary gland development. However, little is known about their roles in bovine lactation process. There are very few reports available to date on the role of lncRNAs in lactation physiology and mammary glands development in cattle. Results To identify and characterize the roles of lncRNAs in bovine lactation, milk derived mammary epithelial cells (MEC) from Jersey (high milk producer) and Kashmiri cattle (low milk producer) at early, mid and late lactation stages were used. The lncRNA transcriptome of the samples (n=18) was studied using next generation RNA sequencing technology. 633 putative lncRNAs were identified, 76 of which were differentially expressed (DE) between comparison between the three stages of lactation. Additionally, 56 DE lncRNAs were identified from 9 Jersey and 9 Kashmir samples. Correlation of DE lncRNAs with protein-coding genes resulted in a comprehensive list of lncRNA-mRNA co-expressed pairs. Most of the DE lncRNAs showed positive correlations with protein coding genes in Jersey compared to Kashmiri cattle where they were mainly negatively correlated, which could be one of the underlying mechanisms responsible for the differential milking performance between the two breeds. In addition, a number of the DE lncRNAs were paired with the most DE milk quality genes like GPAM, LPL, ABCG2, etc. indicative of their potential regulatory effects on milk quality genes. KEGG pathways analysis of potential cis and trans target genes of DE lncRNAs indicated that 27 and 48 pathways were significantly enriched in Kashmiri and Jersey respectively, including mTOR signaling, PI3K-Akt signaling and RAP1 signaling pathways. These pathways have been proven to play key roles in lactation biology and mammary gland development. Conclusions Our study mapped the expression profiles of lncRNAs across lactation stages and their relationships with candidate genes related to milk quality and yield traits in Jersey and Kashmiri cattle. These findings provide a valuable resource for the study of the regulatory mechanisms involved in the lactation process as well as facilitate understanding of the role of lncRNAs in bovine lactation biology.

scholarly journals Characterization of intermediate-sized insertions using whole genome sequencing data and analysis of their functional impacts on gene expression

2021 ◽  
Author(s):  
Saeideh Ashouri ◽  
Jing Hao Wong ◽  
Hidewaki Nakagawa ◽  
Mihoko Shimada ◽  
Katsushi Tokunaga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Gene Expression Regulation ◽  
Regulatory Elements ◽  
Expression Regulation ◽  
Ctcf Binding ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data

Abstract Intermediate-sized insertions are one of the structural variants contributing to genome diversity. However, due to technical difficulties in identifying them, their importance in disease pathogenicity and gene expression regulation remains unclear. We used whole-genome sequencing data of 174 Japanese samples to characterize intermediate-sized insertions using a highly-accurate insertion calling method (IMSindel software and joint-call recovery) and obtained a catalogue of 4,254 insertions. We constructed an imputation panel comprising of insertions and SNVs from all samples, and conducted imputation of intermediate-sized insertions for 82 publicly-available Japanese samples. Imputation accuracy, evaluated using Nanopore long-read sequencing data, was 97%. Subsequent eQTL analysis predicted 128 (~ 3.0%) insertions as causative for gene expression level changes. Enrichment analysis of causal insertions for genome regulatory elements showed significant associations with CTCF-binding sites, super-enhancers, and promoters. Among 17 causal insertions found in the same causal set with GWAS hits, there were insertions associated with changes in expression of cancer-related genes such as BRCA1, ZNF222, and ABCB10. Analysis of insertions sequences revealed that 461 insertions were short tandem duplications frequently found in early replicating regions of genome. Furthermore, comparison of functional importance of intermediate-sized insertions with that of intermediate-sized deletions detected in the same sample set in our previous study showed that insertions were more frequent in genic regions, and proportion of functional candidates was smaller in insertions. Here, we characterize a high-confidence set of intermediate-sized insertions and indicate their importance in gene expression regulation. Our results emphasize the importance of considering intermediate-sized insertions in trait association studies.

scholarly journals Insilco Analysis of Leishmania donovani Genome to Understand its Gene Expression Regulation

2021 ◽  
Author(s):  
Kefiyalew Jote ◽  
Mulugeta Kebede ◽  
Ashenafi Milkessa
Keyword(s):  
Gene Expression ◽  
Leishmania Donovani ◽  
Gene Expression Regulation ◽  
Cpg Island ◽  
Restriction Analysis ◽  
Regulatory Elements ◽  
Expression Regulation ◽  
Promoter Regions ◽  
Body Regions ◽  
Its Gene

Abstract Leishmania donovani is an obligate intracellular parasite of human that causes a dreadful visceral infection that may involve liver, spleen, bone marrow, and lymph nodes. The specific feature of the species influences its genetics. Changes in parasite adaptation to different environment, development of silent genes and parasite progression through its lifecycle may be determined by transcriptional organizations affecting its gene expression. Hence, Insilco analysis of Leishmania donovani BPK282A1 genome was performed to predict the promoter and regulatory elements involved in gene expression. Forty putative genes of Leishmania donovani BPK282A1 genes were obtained from National Center for Biotechnology Information and investigated using bioinformatic tools, such as Neural Network Promoter Prediction, MEME suite, CpG island finder, GOMo and CLC Genomics Workbench. In this analysis, the number of Transcription Start Sites (TSSs) in promoter regions of Leishmania donovani BPK282A1 varied greatly between 1 and 4 with majority (60%) of them having two or more TSSs. The study also revealed seven candidate motifs in the promoter regions of the gene. The common promoter motif for all Leishmania donovani BPK282A1 genes was MI with an E-value of 4.0e-116. Six of the identified motifs were related to zinc finger proteins that bind to the GC-rich regions in DNA. The study also revealed that most of both the promoter and the gene body regions contain at least one CpG island. Restriction analysis using MspI enzyme showed that Leishmania donovani BPK282A1 genes were CpG rich. In conclusion, the investigation unfolded expression regulation of Leishmania donovani BPK282A1 genes contributing to development of a robust drug and vaccine that targets the regulatory regions.

scholarly journals Intronic miRNA Mediated Gene Expression Regulation Controls Protein Crowding Inside the Cell

2018 ◽  
Author(s):  
Prashant Sinha ◽  
Pragya Jaiswal ◽  
Ashwin K. Jainarayanan ◽  
Samir K. Brahmachari
Keyword(s):  
Gene Expression ◽  
Gene Expression Regulation ◽  
Molecular Transport ◽  
Mrna Translation ◽  
Expression Regulation ◽  
Translation Regulation ◽  
Expression Of Genes ◽  
Cellular Machinery ◽  
Regulatory Effects ◽  
Protein Crowding

SUMMARYGene regulatory effects of microRNAs at a posttranscriptional level has been established over the last decade. In this study, we analyze the interaction networks of mRNA translation regulation through intronic miRNA, under various tissue-specific cellular contexts, taking into account the thermodynamic affinity, kinetics, and the presence of competitive interactors. This database, and analysis has been made available through an open-access web-server, miRiam, to promote further exploration.Here we report that expression of genes involved in Apoptosis Processes, Immune System Processes, Translation Regulator Activities, and Molecular Transport Activities within the cell are predominately regulated by miRNA mediation. Our findings further indicate that this regulatory effect has a profound effect in controlling protein crowding inside the cell. A miRNA mediated gene expression regulation serves as a temporal regulator, allowing the cellular machinery to temporarily ‘pause’ the translation of mRNA, indicating that the miRNA–mRNA interactions may be important for governing the optimal usage of cell volume.

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