scRNA-seq and scATAC-seq analyses highlight the role of TNF signaling pathway in chronic obstructive pulmonary disease model mice

Qiang Zhang; Li Zhou; Lindong Yuan; Ruihua Zhang; Shanshan Pan; Xizi Wang; Lili Yi; Fengjiao Yuan; Xianchao Guo; Mingliang Gu; Yan Wang; Xiaodong Jia

doi:10.1371/journal.pone.0322538

Peer Review History

Original SubmissionSeptember 8, 2024
8 Sep 2024 Author Response https://doi.org/10.1371/journal.pone.0322538.r001
6 Nov 2024 Decision Letter - Guanghui Liu, Editor PONE-D-24-39675scRNA-seq and scATAC-seq analyses highlight the role of TNF signaling pathway in chronic obstructive pulmonary disease model micePLOS ONE Dear Dr. Jia, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Dec 21 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This manuscript explores the role of the TNF signaling pathway in chronic obstructive pulmonary disease (COPD) using scRNA-seq and scATAC-seq analyses in model mice. The integration of these high-throughput techniques provides a comprehensive view of the transcriptomic and chromatin accessibility changes associated with COPD, focusing particularly on the TNF pathway's role in inflammation and immune cell function. The study is methodologically sound, and the findings are significant as they contribute to understanding the molecular mechanisms underpinning COPD, potentially guiding targeted therapies. The dual use of scRNA-seq and scATAC-seq provides a robust dataset for analyzing gene expression and regulatory elements in COPD.Detailed methodological description enhances the reproducibility of the research.Significant insights into the role of the TNF signaling pathway in COPD pathogenesis, supported by comprehensive data analysis. The manuscript would benefit from a more extensive review of the literature on TNF signaling in other inflammatory and pulmonary conditions to position its findings within a broader context. In the introduction, mode details should be mentioned for cancer treatment, such as referring to “Cancer treatments: Past, present, and future, 2024”. Additional comparisons with other studies that have used similar methodologies in different diseases could highlight the unique contributions of this work to the field of pulmonary research. The paper should refer to other studies using scRNA seq analysis, such as “Identification of the novel exhausted T cell CD8 + markers in breast cancer, 2024” and scATAC-seq such as “Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Human Developmental Hematopoiesis, 2021” The manuscript presents valuable findings that add significantly to our understanding of the molecular underpinnings of COPD, particularly through the lens of the TNF signaling pathway. However, enhancing the literature review, providing more detailed methodological justifications, and expanding on the clinical implications and limitations of the study would improve its impact and relevance. These improvements would not only solidify the current findings but also help pave the way for future research and potential clinical applications. Reviewer #2: 1. In the abstract section, the term scATAC should not be abbreviated at first mention. 2. In the introduction L 48, the HHIP should be given completely when first mentioned. 3.From line 56 to L 66, the paragraph is mostly methodology and conclusion. The purpose of the study is not elaborated. The same goes to the importance of HHIP and scATAC in COPD study. 4. Do you think 2 mice for each group is enough for accurate experiment and data? 5. The discussion is general and mostly repeating to results. You need to signify each of the parameters studied in initiating COPD. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: Yes: Lei Zhang Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. 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Revision 1
21 Nov 2024 Author Response Reviewer #1: This manuscript explores the role of the TNF signaling pathway in chronic obstructive pulmonary disease (COPD) using scRNA-seq and scATAC-seq analyses in model mice. The integration of these high-throughput techniques provides a comprehensive view of the transcriptomic and chromatin accessibility changes associated with COPD, focusing particularly on the TNF pathway's role in inflammation and immune cell function. The study is methodologically sound, and the findings are significant as they contribute to understanding the molecular mechanisms underpinning COPD, potentially guiding targeted therapies. The dual use of scRNA-seq and scATAC-seq provides a robust dataset for analyzing gene expression and regulatory elements in COPD.Detailed methodological description enhances the reproducibility of the research.Significant insights into the role of the TNF signaling pathway in COPD pathogenesis, supported by comprehensive data analysis. The manuscript would benefit from a more extensive review of the literature on TNF signaling in other inflammatory and pulmonary conditions to position its findings within a broader context. In the introduction, mode details should be mentioned for cancer treatment, such as referring to “Cancer treatments: Past, present, and future, 2024”. Response: Thank you for your comments. As you suggest, we have made revisions in our manuscript, focus on the introduction and discussion sections. We reviewed the relevant literature, and added the relevant studies on TNF signaling pathway in diseases, such as cancer (Lung cancer, Breast cancer), allergic asthmatic, and lung injury. Additional comparisons with other studies that have used similar methodologies in different diseases could highlight the unique contributions of this work to the field of pulmonary research. The paper should refer to other studies using scRNA seq analysis, such as “Identification of the novel exhausted T cell CD8 + markers in breast cancer, 2024” and scATAC-seq such as “Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Human Developmental Hematopoiesis, 2021” Response: Thank you for your comments. We have read the reference “Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Human Developmental Hematopoiesis, 2021”. The data analysis strategy of the reference is basically the same as our data analysis strategy, only the subheadings of each method are named differently. For example, “Upstream analysis of RNA-Seq data” mentioned in the reference corresponds to our method “RNA-Seq raw data processing”; “Upstream analysis of scATAC-Seq data” corresponding to our method “scATAC-seq data pre-processing” and “scATAC-seq quality control”; “Dimensionality reduction of scATAC-Seq data” corresponding to our method “scATAC-seq batch alignment and dimensionality reduction”; “Cell type classification” corresponding to our method “scRNA-seq cell clustering and identification”; “Differential expression analysis” corresponding to our method “DEG identification and analysis”; “Integration of scRNA-Seq and scATAC-Seq data” corresponding to our method “scATAC-seq and scRNA-seq dataset integration”. The manuscript presents valuable findings that add significantly to our understanding of the molecular underpinnings of COPD, particularly through the lens of the TNF signaling pathway. However, enhancing the literature review, providing more detailed methodological justifications, and expanding on the clinical implications and limitations of the study would improve its impact and relevance. These improvements would not only solidify the current findings but also help pave the way for future research and potential clinical applications. Response: Thank you for your comments. As you suggest, we reviewed the relevant literature, and supplemented the relevant research on TNF signaling pathway in lung disease. Meanwhile, in the penultimate paragraph of the discussion, we discussed the limitations of this study. Reviewer #2: 1.In the abstract section, the term scATAC should not be abbreviated at first mention. Response: Thank you for your comments. We have added the full name of scATAC. Please see the abstract section. 2. In the introduction L 48, the HHIP should be given completely when first mentioned. Response: Thank you for your comments. We have added HHIP's full name. Please see line 49. 3.From line 56 to L 66, the paragraph is mostly methodology and conclusion. The purpose of the study is not elaborated. The same goes to the importance of HHIP and scATAC in COPD study. Response: Thank you for your comments. We have added the purpose of this study. Please see line 69 to L 71. 4. Do you think 2 mice for each group is enough for accurate experiment and data? Response: As you said, this study included a relatively small sample size. Indeed, We used eight mice (4 male and 4 female) to create animal models. It is a pity that relatively comprehensive experimental arrangements was not performed in the process of model building and sample collection due to feeding, transportation and other reasons. 5. The discussion is general and mostly repeating to results. You need to signify each of the parameters studied in initiating COPD. Response: Thank you for your comments. As you suggest, we have made revisions in our manuscript, focus on the discussion section. Meanwhile, we have added the relevant studies on TNF signaling pathway in lung diseases. Attachments Attachment Submitted filename: Response to Reviewers.doc https://doi.org/10.1371/journal.pone.0322538.r003
10 Mar 2025 Decision Letter - Tomasz W. Kaminski, Editor PONE-D-24-39675R1scRNA-seq and scATAC-seq analyses highlight the role of TNF signaling pathway in chronic obstructive pulmonary disease model micePLOS ONE Dear Dr. Jia, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Apr 24 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Tomasz W. Kaminski Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: All comments have been addressed Reviewer #3: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes Reviewer #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: (No Response) Reviewer #3: In this work, the authors establish and then generate from a mouse COPD model single cell ATAC-seq and RNA-seq datasets. They interrogate these data using an array of current computational biology approaches. They find that immune response cell such as B cells, mononuclear cells/ macrophages and dendritic cells are associated with COPD. They also find that TNF signaling may play a key role in the disease. The work done, beginning with creation of the model, is thorough and the characterizations of the model are, potentially, a worthy contribution. The manuscript is generally well written. Moreover, the authors have been careful to point out the limitations of the study. The major difficulty I have with this work is that, beyond the novel combination of approaches, the authors do not highlight the gap in knowledge that this study’s findings help fill (if any). For example, there is previous evidence of an association of TNF signaling with COPD in the literature, so there is a need to highlight what is novel here. Some suggested edits: -pages need to be numbered -on line 198, regarding the use of the Seurat package’s FindAllMarkers function, it is not specified what test was used (for example Wilcox, t-test, DESeq2, or other) -on line 200, enrichKEGG from clusterProfiler could not have been used for Gene Ontology enrichment -on line 210, please specify the source of the addGeneIntegrationMatrix function i.e. ArchR -on line 265 “based” should replace “base” -on line 286 “There are color represents” needs to be corrected -lines 309 -312: please specify the figure numbers that are relevant here (was it Figure 3d?). Indeed in much of the Discussion section, refernces to results are made without stating what the associated Figure numbers are -lines 323 et seq: Mouse gene symbols should be “Sox7, Hoxa5”, etc… rather than the human “SOX7, HOXA5”, etc.. as was stated. Moreover, gene symbols need to be italicized -lines 409 – 417: A number of major statements are made without the requisite literature citations ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #2: Yes: Rebah N. Algafari Reviewer #3: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0322538.r004
Revision 2
20 Mar 2025 Author Response Reviewer #3: In this work, the authors establish and then generate from a mouse COPD model single cell ATAC-seq and RNA-seq datasets. They interrogate these data using an array of current computational biology approaches. They find that immune response cell such as B cells, mononuclear cells/ macrophages and dendritic cells are associated with COPD. They also find that TNF signaling may play a key role in the disease. The work done, beginning with creation of the model, is thorough and the characterizations of the model are, potentially, a worthy contribution. The manuscript is generally well written. Moreover, the authors have been careful to point out the limitations of the study. The major difficulty I have with this work is that, beyond the novel combination of approaches, the authors do not highlight the gap in knowledge that this study’s findings help fill (if any). For example, there is previous evidence of an association of TNF signaling with COPD in the literature, so there is a need to highlight what is novel here. Response: Thank you for your comment. As you said, we do not highlight the gap in knowledge that our study’s findings help fill. Indeed, animal models and research methods are the innovations of our study. Our study provides the data of scRNA-seq and scATAC-seq for COPD model mice. Through the joint analysis of scRNA-seq and scATAC-seq, the cell map was systematically mapped, and from the aspects of differential genes, signaling pathways and cell communication to understand the pathogenesis of COPD. TNF signaling has been reported to be associated with COPD. Our study also found that TNF signaling, which is consistent with previous studies. In the last paragraph of the introduction, the first and last paragraph of the discussion section, we describe the key points and key results of this study. Some suggested edits: -pages need to be numbered Response: Thank you for your comments. We paginated our manuscript. -on line 198, regarding the use of the Seurat package’s FindAllMarkers function, it is not specified what test was used (for example Wilcox, t-test, DESeq2, or other) Response: Thank you for your comment. In our analysis using the FindAllMarkers function from the Seurat package, we used the default statistical test, which is the Wilcoxon rank-sum test (as documented in Seurat). This method identifies differentially expressed genes between clusters. We have made revisions in our manuscript. -on line 200, enrichKEGG from clusterProfiler could not have been used for Gene Ontology enrichment Response: Thank you for your comment. You are absolutely correct that the enrichKEGG function from the clusterProfiler package is specifically designed for KEGG pathway enrichment analysis and cannot be used for Gene Ontology (GO) enrichment. For our GO enrichment analysis, we actually used the enrichGO function from clusterProfiler. We acknowledge that this was not clearly described in the original manuscript, which may have caused confusion. As you suggest, we have made revisions in our manuscript. -on line 210, please specify the source of the addGeneIntegrationMatrix function i.e. ArchR Response: Thank you for your suggestion. We confirm that the addGeneIntegrationMatrix function is from the ArchR package. We agree that explicitly stating the source would enhance the clarity of the manuscript. Therefore, we have updated the text. -on line 265 “based” should replace “base” Response: Thank you for your comments. We have made revisions in our manuscript. -on line 286 “There are color represents” needs to be corrected Response: Thank you for your comments. We have made revisions in our manuscript. -lines 309 -312: please specify the figure numbers that are relevant here (was it Figure 3d?). Indeed in much of the Discussion section, refernces to results are made without stating what the associated Figure numbers are Response: Thank you for your comments. As you suggest, we have made revisions in our manuscript. -lines 323 et seq: Mouse gene symbols should be “Sox7, Hoxa5”, etc… rather than the human “SOX7, HOXA5”, etc.. as was stated. Moreover, gene symbols need to be italicized Response: Thank you for your comments. We have made revisions in our manuscript (line 323). Meanwhile, the gene symbols that appear in our manuscript are shown in italics. -lines 409 – 417: A number of major statements are made without the requisite literature citations Response: Thank you for your comments. As you suggest, We have added the relevant references. Attachments Attachment Submitted filename: Response_to_Reviewers_auresp_2.doc https://doi.org/10.1371/journal.pone.0322538.r005
25 Mar 2025 Decision Letter - Tomasz W. Kaminski, Editor scRNA-seq and scATAC-seq analyses highlight the role of TNF signaling pathway in chronic obstructive pulmonary disease model mice PONE-D-24-39675R2 Dear Dr. Jia, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Tomasz W. Kaminski Academic Editor PLOS ONE Additional Editor Comments (optional): Thank you for submitting the revised version of your manuscript. After reviewing the changes, I confirm that all the minor issues raised in the previous round have been addressed. The manuscript is now suitable for acceptance. Please note that there are still some minor typos that will need to be corrected during the proofreading stage. Otherwise, no further revisions are required. Best Regards. https://doi.org/10.1371/journal.pone.0322538.r006
Formally Accepted
Acceptance Letter - Tomasz W. Kaminski, Editor PONE-D-24-39675R2 PLOS ONE Dear Dr. Jia, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Tomasz W. Kaminski Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0322538.r007

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