H3K4 Methylation in Aging and Metabolism

Round 1

Reviewer 1 Report

Globally a well-written review on the correlation between H3K4me, metabolites levels and ageing. However, as a histone mark H3K4me doesn't do much (i.e. methylation doesn't change the charge of modified lysine, doesn't lead to chromatin remodelling by itself, or impact on nucleosome structure). Thus, it would be important to at least mention a few H3K4me readers and discuss their role during ageing (and progeria syndromes?).

A few minor corrections:

Typo line 106 sties -> sites

Line 138, correct "is also involved IN various".

Line 314, do the author mean S-SAM or SAM?

Author Response

Responses to reviewers’ comments:

Reviewer 1:

Comments and Suggestions for Authors

Globally a well-written review on the correlation between H3K4me, metabolites levels and ageing. However, as a histone mark H3K4me doesn't do much (i.e. methylation doesn't change the charge of modified lysine, doesn't lead to chromatin remodelling by itself, or impact on nucleosome structure). Thus, it would be important to at least mention a few H3K4me readers and discuss their role during ageing (and progeria syndromes?).

Response:

We thank the reviewer for bringing up this important issue. As we described in section 4.2, it is evident that a limited amount of this modification is favorable for optimal C. elegans life span. However, it is still unclear how reduced levels of H3K4me3 increase longevity, and the functional implications of large-scale epigenomic alterations in senescent human cells are also unknown. Furthermore, there is no report linking H3K4me readers to aging. We thus propose that the breadth of H3K4me3 deposited on gene promoters could influence expression of particular gene sets, which may lead to the cellular phenotypes observed during senescence/aging. In this revision, we have added an alternative possibility that the profound change in H3K4 methylation distribution may contribute to genome reorganization. The details of this possibility are included in section 4.4 of the revised text.

A few minor corrections:

Typo line 106 sties -> sites Corrected.

Line 138, correct "is also involved IN various". Corrected.

Line 314, do the author mean S-SAM or SAM? Corrected.

Reviewer 2:

Comments and Suggestions for Authors

Overview and general recommendation:

Hsu et al. have written an insightful review on H3K4 methylation’s putative role in aging which covers different species and has a special focus on metabolism. Reviews on these particular topics in combination are lacking, and as this paper compiles recent, as well as important, papers in the field I believe this publication will be well received and impactful. The discussion is well-thought out and laid out for the reader. I do believe some improvements could be made to the visualization, the included references and some additional aspects should be covered in order for this to be a more well-rounded.

Minor Comments

 In section 5, lines 236-302, the authors cover the involvement of H3K4 methylation in aging of different species. They include a variety of species in order of complexity but the transition from C elegans/ Drospophila to Humans appears to be missing intermediate model organisms which have been important to the field, such as the mouse. There are abundant and well-cited aging studies in the mouse models in a variety of tissues, covering epigenetic profiling, particularly in H3K4me3. Dietary restriction is well controlled and studied in the mouse model (e.g. Sun D et al., 2014, Cao Q et al., 2020 or Sleiman MB et al., 2020). The authors should include a section on mammalian models, in particular the mouse.

Response:

We agree and thank the reviewer for providing relevant references. A new section to discuss aging studies in the mouse model has been included in the revised text (section 4.3). Although the transcriptional regulation through H3K4me3 methylation is well covered in this review, the authors limit discussion independent of other histone marks. Bivalent marks, particularly H3K4me3 and H3K27me3 have been shown to be preferential sites of epigenetic changes during aging (e.g. Hahn O et al., 2017, Cole JJ et al., 2017). This should be included to provide a picture of how complex and well-controlled epigenetic marks are and how the deregulation of this balance contributes to aging.

Response:

The dynamics of bivalent marks is an intriguing concept in aging research. We have included a new paragraph in the new section 4.4 to introduce the possibility of aging-related transformation of bivalent marks in the chromatin environment. Figure 3 is a useful one but would have more benefit being split into two distinct figures. One which covers the involvement of H3K4 methylation in cellular processes, e.g. transcriptional activation, replication and DNA damage response, which should be placed near section 3; and another which covers the deregulation of H3K levels or locations during aging and how this is likely to contribute to aging phenotypes (to remain at line 472).

Response:

As suggested, a new Figure 4 has been added to illustrate the deregulation of H3K4 methylation during aging processes. In lines 35-38, the authors refer to the programmed aging theory as the being currently well-accepted. There is still some debate around programmed vs random theories of aging. It would be just for the authors to discuss this, and, if leaning towards the programmed theory, to illustrate evidence by citing more than the one paper/review.

Response:

We believe that aging is a complex molecular program, largely because researchers have been able to increase/decrease lifespans of model organisms by numerous

Reviewer 2 Report

Overview and general recommendation:

Hsu et al. have written an insightful review on H3K4 methylation’s putative role in aging which covers different species and has a special focus on metabolism. Reviews on these particular topics in combination are lacking, and as this paper compiles recent, as well as important, papers in the field I believe this publication will be well received and impactful. The discussion is well-thought out and laid out for the reader. I do believe some improvements could be made to the visualization, the included references and some additional aspects should be covered in order for this to be a more well-rounded.

Minor Comments

In section 5, lines 236-302, the authors cover the involvement of H3K4 methylation in aging of different species. They include a variety of species in order of complexity but the transition from C elegans/ Drospophila to Humans appears to be missing intermediate model organisms which have been important to the field, such as the mouse. There are abundant and well-cited aging studies in the mouse models in a variety of tissues, covering epigenetic profiling, particularly in H3K4me3. Dietary restriction is well controlled and studied in the mouse model (e.g. Sun D et al., 2014, Cao Q et al., 2020 or Sleiman MB et al., 2020). The authors should include a section on mammalian models, in particular the mouse.

Although the transcriptional regulation through H3K4me3 methylation is well covered in this review, the authors limit discussion independent of other histone marks. Bivalent marks, particularly H3K4me3 and H3K27me3 have been shown to be preferential sites of epigenetic changes during aging (e.g. Hahn O et al., 2017, Cole JJ et al., 2017). This should be included to provide a picture of how complex and well-controlled epigenetic marks are and how the deregulation of this balance contributes to aging.

Figure 3 is a useful one but would have more benefit being split into two distinct figures. One which covers the involvement of H3K4 methylation in cellular processes, e.g. transcriptional activation, replication and DNA damage response, which should be placed near section 3; and another which covers the deregulation of H3K levels or locations during aging and how this is likely to contribute to aging phenotypes (to remain at line 472).

In lines 35-38, the authors refer to the programmed aging theory as the being currently well-accepted. There is still some debate around programmed vs random theories of aging. It would be just for the authors to discuss this, and, if leaning towards the programmed theory, to illustrate evidence by citing more than the one paper/review.

Lines 138-140, more background on “origin fitting” in the context of replication and H3K4 methylation is needed as researchers well-versed in epigenetic regulation may not necessarily be so well versed in the details of replication regulation.

Likewise in lines 164-165, the authors should expand on the differences reported on the proposed mechanisms of benomyl resistance phenotypes as reported in the reference

Author Response

Responses to reviewers’ comments:

Reviewer 1:

Comments and Suggestions for Authors

Globally a well-written review on the correlation between H3K4me, metabolites levels and ageing. However, as a histone mark H3K4me doesn't do much (i.e. methylation doesn't change the charge of modified lysine, doesn't lead to chromatin remodelling by itself, or impact on nucleosome structure). Thus, it would be important to at least mention a few H3K4me readers and discuss their role during ageing (and progeria syndromes?).

Response:

We thank the reviewer for bringing up this important issue. As we described in section 4.2, it is evident that a limited amount of this modification is favorable for optimal C. elegans life span. However, it is still unclear how reduced levels of H3K4me3 increase longevity, and the functional implications of large-scale epigenomic alterations in senescent human cells are also unknown. Furthermore, there is no report linking H3K4me readers to aging. We thus propose that the breadth of H3K4me3 deposited on gene promoters could influence expression of particular gene sets, which may lead to the cellular phenotypes observed during senescence/aging. In this revision, we have added an alternative possibility that the profound change in H3K4 methylation distribution may contribute to genome reorganization. The details of this possibility are included in section 4.4 of the revised text.

A few minor corrections:

Typo line 106 sties -> sites Corrected.

Line 138, correct "is also involved IN various". Corrected.

Line 314, do the author mean S-SAM or SAM? Corrected.

Reviewer 2:

Comments and Suggestions for Authors

Overview and general recommendation:

Hsu et al. have written an insightful review on H3K4 methylation’s putative role in aging which covers different species and has a special focus on metabolism. Reviews on these particular topics in combination are lacking, and as this paper compiles recent, as well as important, papers in the field I believe this publication will be well received and impactful. The discussion is well-thought out and laid out for the reader. I do believe some improvements could be made to the visualization, the included references and some additional aspects should be covered in order for this to be a more well-rounded.

Minor Comments

In section 5, lines 236-302, the authors cover the involvement of H3K4 methylation in aging of different species. They include a variety of species in order of complexity but the transition from C elegans/ Drospophila to Humans appears to be missing intermediate model organisms which have been important to the field, such as the mouse. There are abundant and well-cited aging studies in the mouse models in a variety of tissues, covering epigenetic profiling, particularly in H3K4me3. Dietary restriction is well controlled and studied in the mouse model (e.g. Sun D et al., 2014, Cao Q et al., 2020 or Sleiman MB et al., 2020). The authors should include a section on mammalian models, in particular the mouse.

Response:

We agree and thank the reviewer for providing relevant references. A new section to discuss aging studies in the mouse model has been included in the revised text (section 4.3). Although the transcriptional regulation through H3K4me3 methylation is well covered in this review, the authors limit discussion independent of other histone marks. Bivalent marks, particularly H3K4me3 and H3K27me3 have been shown to be preferential sites of epigenetic changes during aging (e.g. Hahn O et al., 2017, Cole JJ et al., 2017). This should be included to provide a picture of how complex and well-controlled epigenetic marks are and how the deregulation of this balance contributes to aging.

Response:

The dynamics of bivalent marks is an intriguing concept in aging research. We have included a new paragraph in the new section 4.4 to introduce the possibility of aging-related transformation of bivalent marks in the chromatin environment. Figure 3 is a useful one but would have more benefit being split into two distinct figures. One which covers the involvement of H3K4 methylation in cellular processes, e.g. transcriptional activation, replication and DNA damage response, which should be placed near section 3; and another which covers the deregulation of H3K levels or locations during aging and how this is likely to contribute to aging phenotypes (to remain at line 472).

Response:

As suggested, a new Figure 4 has been added to illustrate the deregulation of H3K4 methylation during aging processes. In lines 35-38, the authors refer to the programmed aging theory as the being currently well-accepted. There is still some debate around programmed vs random theories of aging. It would be just for the authors to discuss this, and, if leaning towards the programmed theory, to illustrate evidence by citing more than the one paper/review.

Response:

We believe that aging is a complex molecular program, largely because researchers have been able to increase/decrease lifespans of model organisms by numerous