Evaluated articles

Evaluation Summary:

This paper will be of interest to the chromosome biology field and SMC researchers in particular. The study provides cell biological, biochemical, and structural modeling evidence that a new Nse5-like protein named SIMC1 is a paralog of SLF1, and that the two compete for SLF2-Smc5/6 binding. The authors also show that SIMC1 targets SMC5/6 to polyomavirus replication centers through its SUMO binding motifs (SIMs), supporting a role for SIMC1 in Smc5/6 recruitment for viral restriction.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Burl and Rondini et al. elucidate the transcriptional profile of the stromal vascular fraction of murine brown adipose tissue in the context of thermogenic stimulation. The authors combined systems and reductionist approaches to show the reliance of mature brown adipocytes on adrenergic activation to indirectly stimulate progenitor proliferation and differentiation and the involvement of dendritic cells in this process. Overall, this is a timely and well-rounded work that will provide beneficial data for public use and further resolve the complexities underlying brown adipose physiology.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper is one of the first demonstrations that expression quantitative trait loci (eQTL) affecting human microRNAs are linked to brain development affecting brain structure and function. These findings will have a broad impact on the genomics, neural development, and microRNA fields. The datasets produced here (developmental changes in miRNAs, new human miRNAs) will likely be used for further discoveries. However, some claims need to be tempered.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

DNA methylation inheritance through the UHRF1-DNMT1 signaling axis is becoming increasingly appreciated as a ubiquitin-regulated process. This study builds on the observation that UHRF1 multi mono-ubiquitinates the PCNA-associated protein PAF15, and that, similarly to H3 substrates, these mono-ubiquitin sites are bound by DNMT1 and may contribute to its S-phase chromatin association. The authors focus on players involved in ubiquitin removal and PAF15 release from chromatin and they identify the deubiquitinase USP7 and the DNA replication regulator ATAD5 as important to this termination process. While manipulation of these factors using Xenopus egg extracts shows quite striking effects on DNMT1 chromatin association, effects on DNA methylation are minimal and this brings to question the importance and potential impact of the pathway involving PAF15. In addition, how the findings from Xenopus egg extracts translate to regulation of DNA methylation maintenance in mammalian cells is currently unclear.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This study evaluates the effects of two distinct dietary methods that cause obesity in mice (high fat vs high starch) on insulin sensitivity and glucose homeostasis. Through a series of nicely performed physiology experiments, the authors demonstrated that high starch feeding causes obesity without deleterious effects on insulin sensitivity. This work will have an impact in the field and help define the important lipid mediators of metabolic disease.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper presents a novel and potentially highly useful approach to monitor circadian rhythms in specific tissues. The elegant reporter that the authors have built has the potential to become an important tool for understanding how different body clocks respond to various inputs and genetic manipulations. The authors already apply it to show that different clocks appear to be responding differently to loss of signaling from a key circadian neuropeptide in Drosophila melanogaster. However, it is difficult to determine whether these results, as currently presented and analyzed, provide new insight into the relationship between brain and peripheral clocks. The work is of interest to the community of biologists studying biological rhythms.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Predicting if a tumour has aggressive or metastatic characteristics would be of great utility in the clinic as it would help patient stratification and management. In this manuscript, Carrier and collaborators derive a signature for melanoma aggressiveness relying on methylated regions of tumour and cell line genomes. The identification of a 4-gene methylation biomarker for melanoma aggressiveness and survival is an important contribution. This manuscript is of relevance to clinicians and melanoma researchers interested in biomarker research.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This is an important paper querying odor responses in the olfactory bulb at low concentrations. Classical studies have revealed a 'combinatorial code' for odorant recognition, with individual odorants represented by combinations of broadly tuned and low-affinity olfactory receptors. Here, the authors perform a large-scale analysis of odor responses across glomeruli and surprisingly observe that odorant receptors instead generally display remarkably narrow tuning profiles.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This paper shows that Drosophila can perform olfactory unimodal sensory preconditioning, an example of higher-order conditioning that may guide behaviour through inferred value. This is of conceptual significance for the brain, behavioural, and to some extent, the social sciences, because it shows that a conditioned response to a stimulus can occur even when the stimulus itself was never paired with punishment, for example.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This submission represents a holistic approach to how pentraxin 3 (PTX3) modulates susceptibility to experimental infection by Streptococcus pneumoniae. The authors have built robust findings on the importance of PTX3 for the survival of mice and they have extensively investigated all different aspects of the mechanism of PTX3 protection. One main strength of the manuscript is its usage of bone marrow chimeras in addition to total as well as tissue-specific mouse strains that support their claims.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

In this paper, the authors demonstrate that a reversible amination network that allows nitrogen transfer via transaminases for synthesis of several amino acids can be constructed in laboratory strains through clever and carefully designed experiments. As a result, this work should be of interest to microbiologists, biochemists, synthetic biologists, and biotechnologists.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

Nicastro et al. uncover a new input for the central metabolic regulator TOR complex 1 (TORC1) , namely manganese (Mn) levels, in budding yeast and they show that this dependence on Mn is conserved in humans. TORC1 is a central coordinator of multiple inputs to guide cellular decisions of catabolism vs anabolism, and information on an additional way to modulate its activity will be highly influential in both basic cell biology as well as therapeutic research.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1

Evaluation Summary:

Mitochondria have their own DNA, which is much more likely to gain mutation (due to error-prone DNA polymerase). It is widely appreciated that there are quality control mechanisms such that functional mitochondria are passed from one generation to the next. The proposed mechanisms include a passive mechanism (generation of the bottleneck) as well as an active mechanism (selective removal of non-functional mitochondria), but the processes are not fully understood. This manuscript presents fascinating observations as to how C. elegans germline may remove mitochondria by creating bottlenecks as well as selectively removing non-functional mitochondria. Building upon the authors' previous finding that the C. elegans primordial germ cells (PGCs) shed much of cytoplasm during embryogenesis through 'cannibalism', they now describe that a bulk of mitochondria are removed from PGCs through this process.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This paper proposes a novel mechanism used by the visual system to recruit interneurons into the visual thalamus. The primary claims that retinal ganglion cell axons secrete Shh in the visual thalamus that induces FGF15 expression by astrocytes, that then attract interneurons are sound. Because Shh signaling, interneuron migration, and astrocyte functions are studied by a large number of neuroscientists this study will have a high impact on the field.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

The authors use single-cell RNA-sequencing, single-cell ATAC-sequencing, a CRISPR-based lineage tracing system, and a novel computational pipeline to characterize heritable expression changes. Aspects of this work were found to be both impactful and technically sound, but there is a concern with the scalability/generalizability of the approach, the use of the single cell ATAC-sequencing data, and some technical aspects of the computational pipeline. This work will appeal to groups working on lineage tracing and gene regulation.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors show that a widely used knock-out mouse for Mertk carries multiple additional changes in its genome, affecting the expression of a number of genes besides Mertk. They show that, although the line was back-crossed to the C57 background, these changes are due to the original 129P2 genome of the embryonic stem cells in which the knock-out was originally created. Through the generation of two new knock-out mouse strains, in C57 embryonic stem cells, the authors here show only part of the phenotype of the original Mertk knock-out mouse can be reproduced. Overall, this study raises awareness as to the limitations of the Mertk-/- v1 model and limits direct inference of Mertk-/-v1 observed phenotypes to Mertk deficiency alone.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors here present how specific fatty acids modulate the bactericidal effect of the antibiotic vancomycin. The authors find that palmitoleic acid significantly increases the bactericidal activity of vancomycin and investigate the mechanism responsible. The key finding will be of interest to a broad audience of researchers focused on microbiology, host-pathogen interactions, and antimicrobial development, as well as to clinicians that treat antibiotic-recalcitrant infections.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

Prostate cancer cellular heterogeneity is a major problem for disease progression and treatment resistance. This body of work addresses the cellular identity and populations that make up prostate cancer using single-cell sequencing technology and state-of-the-art mouse models. The cellular identities, associated signaling networks, and immune complexes accompanying the heterogeneity of the prostate are identified in this work and a resource is provided for scientists in the field.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This study reports on the diagnostic utility of TRIO-based whole-exome sequencing (WES) in a cohort of 123 unrelated patients with suspected monogenic inborn errors of immunity. The authors further explored the diagnostic rate in this cohort by focusing their analyses on the identification of de novo variants (DNVs). This manuscript will be of interest to medical geneticists, immunologists, and physicians working with patients with primary immunodeficiencies.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Monteiro de Assis et al. demonstrate a role for T3 in modulating circadian metabolic rhythms both systemically and within the liver. The findings extend the molecular framework in which organismal metabolism is coordinated in a circadian fashion.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)