Molecular Biology

Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome

1. Kira A Cozzolino
2. Lynn Sanford
3. Samuel Hunter
4. Kayla Molison
5. Benjamin Erickson
6. Meaghan CS Courvan
7. Taylor Jones
8. Deepa Ajit
9. Matthew D Galbraith
10. Joaquín M Espinosa
11. David Bentley
12. Mary Ann Allen
13. Robin D Dowell
14. Dylan J Taatjes

• Curated by eLife

  eLife Assessment

  This is an important study providing compelling evidence that the Mediator kinase module mediates an elevated inflammatory response, manifested by heightened cytokine levels, associated with Downs syndrome (DS) via transcriptional changes impacting cell signaling and metabolism that involve mobilization of nuclear receptors by altered lipid metabolites, which has significance for the treatment of DS and other chronic inflammatory conditions. Particular strengths of the study include the combined experimental approaches of transcriptomics, untargeted metabolomics and cytokine screens and the use of sibling matched cell lines (trisomy 21 vs disomy 21) from various donors. Evidence is also provided implicating the Mediator kinase module in controlling mRNA splicing and mitochondrial function that should stimulate new research to elucidate the mechanistic bases for these novel functions.

Reviewed by eLife

Decoding m6Am by simultaneous transcription-start mapping and methylation quantification

1. Jianheng Fox Liu
2. Ben R Hawley
3. Luke S Nicholson
4. Samie R Jaffrey

• Curated by eLife

  eLife Assessment

  This study presents a new quantitative method, CROWN-seq, to map the cap-adjacent RNA modification N6,2'-O-dimethyladenosine (m6Am) with single nucleotide resolution. Using thoughtful controls and well-validated reagents, the authors provide compelling evidence that the method is reliable and reproducible. Additionally, the study provides important evidence that m6Am may increase transcription in modified mRNAs. However, the data only demonstrates a correlation between m6Am and transcriptional regulation rather than causality. Overall, this study is poised to advance m6Am research, being of broad interest to the RNA biology and gene regulation fields.

Reviewed by eLife

Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex

1. Jittoku Ihara
2. Yibin Huang
3. Yoichi Takami
4. Yoichi Nozato
5. Toshimasa Takahashi
6. Akemi Kakino
7. Cheng Wang
8. Ziwei Wang
9. Yu Guo
10. Weidong Liu
11. Nanxiang Yin
12. Ryoichi Ohara
13. Taku Fujimoto
14. Shino Yoshida
15. Kazuhiro Hongyo
16. Hiroshi Koriyama
17. Hiroshi Akasaka
18. Hikari Takeshita
19. Shinsuke Sakai
20. Kazunori Inoue
21. Yoshitaka Isaka
22. Hiromi Rakugi
23. Tatsuya Sawamura
24. Koichi Yamamoto

• Curated by eLife

  eLife Assessment

  This study provides useful in vitro evidence to support a mechanism whereby dyslipidemia could accelerate renal functional decline through the activation of the AT1R/LOX1 complex by oxLDL and AngII. As such, it improves the knowledge regarding the complex interplay between dyslipidemia and renal disease and provides a solid basis for the discovery of novel therapeutic strategies for patients with lipid disorders. The methods, data, and analyses partly support the presented findings, although the observed variability and need for further in vivo validation require additional research in this key area.

Reviewed by eLife

Structure-based mechanism of RyR channel operation by calcium and magnesium ions

1. Alexandra Zahradníková
2. Jana Pavelková
3. Miroslav Sabo
4. Sefer Baday
5. Ivan Zahradník

Reviewed by Review Commons

eIF3 engages with 3’-UTR termini of highly translated mRNAs

1. Santi Mestre-Fos
2. Lucas Ferguson
3. Marena I Trinidad
4. Nicholas T Ingolia
5. Jamie HD Cate

• Curated by eLife

  eLife Assessment

  This valuable study shows previously unappreciated binding of the eukaryotic translation initiation factor 3 (eIF3) to the poly(A) tail proximal portion of 3' untranslated regions (UTRs) of mRNAs that are efficiently translated in neuronal progenitors. The authors' conclusions are supported by solid experimental evidence which is based on several orthogonal systems biology approaches. This article is of considerable interest to the broad spectrum of biomedical researchers interested in studying post-transcriptional regulation of gene expression.

Reviewed by eLife

Phenotypic impact of individual conserved neuronal microexons and their master regulators in zebrafish

1. Laura Lopez-Blanch
2. Cristina Rodríguez-Marin
3. Federica Mantica
4. Luis P Iñiguez
5. Jon Permanyer
6. Elizabeth M Kita
7. Tahnee Mackensen
8. Mireia Codina-Tobias
9. Francisco Romero-Ferrero
10. Jordi Fernandez-Albert
11. Myriam Cuadrado
12. Xosé R Bustelo
13. Gonzalo G de Polavieja
14. Manuel Irimia

• Curated by eLife

  eLife Assessment

  This study presents important analyses of the impacts of microexon deletions and loss-of-function in microexon regulators on zebrafish neurite outgrowth and gene expression, as well as adult and larval behavior. While microexons have been mapped in many genes several years ago, information on their functions - in particular with regard to individual gene isoforms - is limited. The authors provide convincing evidence that individual microexon deletions, only in a few cases, produce subtle cellular and behavioural phenotypes, while transcriptomic analysis reveals gene expression alterations that are suggestive of compensatory mechanisms that buffer against microexon disruption.

Reviewed by eLife

Neuralized-like proteins differentially activate Notch ligands

1. Alina Airich
2. Oren Gozlan
3. Ekaterina Seib
4. Lena-Sophie Wilschrey
5. Gittel Leah Shaingarten
6. David Sprinzak
7. Thomas Klein

Reviewed by Review Commons

The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2

1. Adam D Longhurst
2. Kyle Wang
3. Harsha Garadi Suresh
4. Mythili Ketavarapu
5. Henry N Ward
6. Ian R Jones
7. Vivek Narayan
8. Frances V Hundley
9. Arshia Zernab Hassan
10. Charles Boone
11. Chad L Myers
12. Yin Shen
13. Vijay Ramani
14. Brenda J Andrews
15. David P Toczyski

• Curated by eLife

  eLife Assessment

  This valuable study reports a chemogenetic screen for resistance and sensitivity to three cell cycle inhibitors used in the clinic: camptothecin, colchicine, and palbociclib. The screen provides a wealth of information that will be of interest to cell cycle and cancer biologists. Convincing evidence is provided that resistance to palbociclib can result from loss of PRC2.1 activity, which raises cyclin D levels. The effect of PRC2.1 on cyclin D is not universal across tested cell lines with the causal differences not yet understood.

Reviewed by eLife

Tom1p ubiquitin ligase structure, interaction with Spt6p, and function in maintaining normal transcript levels and the stability of chromatin in promoters

1. Jennifer Madrigal
2. Heidi L Schubert
3. Matthew A Sdano
4. Laura McCullough
5. Zaily Connell
6. Tim Formosa
7. Christopher P Hill

• Curated by eLife

  eLife Assessment

  This useful manuscript presents findings on Tom1p's interaction with Spt6p and its role in chromatin dynamics, supported by structural analysis through CryoEM. The evidence for the conclusions is currently incomplete, lacking key experiments including continuation in vivo interaction and orthogonal binding assays (e.g., SPR, MST, ITC) to fully support the proposed mechanism. While the results are promising, further validation is needed to strengthen the evidence and improve the manuscript's overall cohesion.

Reviewed by eLife

Ribosomal RNA methylation by GidB modulates discrimination of mischarged tRNA

1. Zhuo Bi
2. Yu-Xiang Chen
3. Iris D Young
4. Hong-Wei Su
5. Yuemeng Chen
6. Jia-Yao Hong
7. James S Fraser
8. Babak Javid

• Curated by eLife

  eLife Assessment

  This important study by Bi and colleagues employed a clever genetics screen to uncover the role of the GidB rRNA methylase in translation fidelity, under certain conditions, in Mycobacterium smegmatis. The findings are solid, supporting the conclusions, but the structural analyses lack the necessary rigor and depth to provide a clear mechanism. The work will be of interest to microbiologists.

Reviewed by eLife