Dear Dr. Drier,

Thank you very much for submitting your manuscript "SARS-CoV-2 infection perturbs transcriptional regulation of lung cells, supporting cell-cell infection, and inducing Wnt signaling, MAPK signaling and pro-inflammatory cytokines" for consideration at PLOS Computational Biology.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Shailendra Shivaji Gurav, PhD

Guest Editor

PLOS Computational Biology

Rob De Boer

Section Editor

PLOS Computational Biology

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Dear Authors,

I have completed my evaluation of your manuscript. The reviewers recommend reconsideration of your manuscript following major revision. I invite you to resubmit your manuscript after addressing the all reviewers comments.

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: 1. Title- It should be simple and clear. Consider modifying it.

2. Short Title- The present short title does not seem to convey the message of this study.

3. Keywords- Keep them specific. Avoid general words like ‘epigenetics’. Words from present title can be projected as keywords provided the title is considered to be modified. It would help to improve the citations of this study.

4. Abstract- It should reflect the summary of the study with 1-2 introductory lines, objective statement, brief methodology, key results, and concluding remarks. This draft seems ambiguous that lacks clarity.

5. Abstract- Avoid abbreviations right away (E.g., WT1). Mention abbreviation in a full form at the first place it appears.

6. Introduction- This section reads incompetent to establish the study. It should contain disease burden, problem statement, and present approaches to address it. It also should introduce the biochemical factors and their significance in disease progression. For example- What is the rational of acetylation in COVID-19 pathogenesis? This section can be concluded with a paragraph emphasizing approach or plan of present study.

7. Results- Figure 1(A) claims to depict the change in H3K27 acetylation in infected cells as compared to uninfected cells. In reality, the figure does not show the data points of acetylation in uninfected cells.

8. Results- Figure 2 conveys the association between acetylation gain and gene upregulation. However, sub-figures (B, C, G, and H) can be represented with bar graph after percent normalization for ease of understanding.

9. Results- A table of pathway regulators is recommended instead of mentioning them all in the text.

10. Results- For figure 4 (C and F), refer comment No. 8.

11. Discussion- This section reads conclusion instead of discussion. This section should discuss the obtained results at the background of available literature. It should identify present research gaps and comment how your observations helped to fill those gaps.

12. Conclusion- This section is major missing.

13. Methodology- Explain the rationale behind every method that was followed.

14. Methodology- It contains the word ‘we’ consistently. Rephrase the sentences and avoid first-person narrative.

15. General- Authors are supposed to be well-versed with the research in this area. The study should establish a rationale or hypothesis properly. There is a great scope of improvement in scientific writing, development of logical methodology, data representation and interpretation.

Reviewer #2: Dear Authors,

The research article under consideration is a nice research work which would prove very useful with challenges we are facing with the pandemic and post pandemic issues. However, this manuscript needs some corrections and revisions as listed below.

The title could be simplified for better understanding, may be avoid more technical terms.

The abstract need revision, it need to reflect the contents and the findings.

Introduction and methodology needs to be more comprehensive.

Please correct grammatical and topological errors.

A takeaway message in form of conclusion would be very helpful.

Thank you

Reviewer #3: Dear authors, I found your draft quite interesting to read and I really loved doing this. However, there are some concerns I couldn’t accept in the present form. I am summarizing few of them below; I hope this would help you for further refinement of your draft.

• Statement “Despite extensive studies of the effects of SARS-CoV-2 infection, we still lack an understanding of the downstream epigenetic and transcriptional alterations” ; however, few information is available- (doi: 10.1016/j.virusres.2022.198853; https://doi.org/10.1186/s13073-022-01137-4; https://doi.org/10.1186/s13148-020-00946-x) I think you need to compare your findings with these evidences

• Figure 1 (b and c) can be revised. I feel you have provided the default images; however, it looks inadequate and can be presented in simpler way

• In table you mention “lower and higher acetylation levels”; what defines this? Is there any threshold to mention whether the acetylation is higher or lower?

• Please avoid providing any references in the results section

• All the Venn diagrams should be revised; the area containing higher items should be larger than another; please revise

• I see your study focuses towards Wnt signaling, MAPK signaling and pro-inflammatory which are also regulated by IFN1. Just out of curiosity, did you found any epigenetic and transcriptional alterations in IFN1 signaling (Jak-STAT)? During viral infection, there is modulation of these pathways to produce vicious cycle in response to infection.

• Figure 3; “Others….” Please name some in foot note of the figure legend

• Please rewrite all the statements in past tense in results and methodology

• Few errors can be observed in phrase and sentences; Please revise

• Figure 4(g) should be revise; GO terms are too close to read

• In methodology; please detail “Acetylation distribution”

• In methodology, “we defined an enrichment fold change score by (target gene in term * total genes)/(total target genes * gene in term)”; How do you define this? Can you provide a reference for it?

Thank you

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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: 

Reviewer #2: Yes:

Reviewer #3: No

Figure 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. 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 us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Dr. Drier,

Thank you very much for submitting your manuscript "SARS-CoV-2 infection perturbs enhancer mediated transcriptional regulation of key pathways" for consideration at PLOS Computational Biology. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Shailendra S. Gurav, PhD

Guest Editor

PLOS Computational Biology

Rob De Boer

Section Editor

PLOS Computational Biology

***********************

A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors seems to complied the review comments. The revised version has the potential to be published.

Reviewer #2: Nice work of revising the draft.

Reviewer #3: Dear authors, I am still puzzled with enrichment fold change score calculation? You responded in line 426-427 but what is the basis for that? Please quote this calculation if not please detail the rationale for this formula for enrichment fold change score. Further, I do not agree on your statement “We believe that it is important to give credit and provide references when it is due” for my query “Please avoid providing any references in the results section”. The result section in the manuscript (research) is only meant to provide the findings of your methodology hence it is called results section. I did not mean not to give the credit but it should be in the order. It would be better you could discuss the finding and quote the statement only in discussion section not in results.

Thanks

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: None

Reviewer #3: None

**********

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: Akash Saggam

Reviewer #2: No

Reviewer #3: No

Figure 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. 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 us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References:

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.

Dear Dr. Drier,

We are pleased to inform you that your manuscript 'SARS-CoV-2 infection perturbs enhancer mediated transcriptional regulation of key pathways' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology. 

Best regards,

Shailendra Shivaji Gurav, PhD

Guest Editor

PLOS Computational Biology

Rob De Boer

Section Editor

PLOS Computational Biology

***********************************************************

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #3: Thanks for providing reference

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

**********

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 #3: No