S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress
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The manuscript proposes a mechanism by which different S-adenosylmethionine (SAM) synthase enzymes exhibit specificity towards target sequences, thereby proposing a novel layer of control over H3K4 trimethylation (H3K4me3). Such specificity is demonstrated in the context of responses to heat stress for two Caenorhabditis elegans SAM synthase enzymes, supporting the existence and importance of this novel mechanism of epigenetic control.
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Abstract
Methylation is a widely occurring modification that requires the methyl donor S-adenosylmethionine (SAM) and acts in regulation of gene expression and other processes. SAM is synthesized from methionine, which is imported or generated through the 1-carbon cycle (1 CC). Alterations in 1 CC function have clear effects on lifespan and stress responses, but the wide distribution of this modification has made identification of specific mechanistic links difficult. Exploiting a dynamic stress-induced transcription model, we find that two SAM synthases in Caenorhabditis elegans , SAMS-1 and SAMS-4 , contribute differently to modification of H3K4me3, gene expression and survival. We find that sams-4 enhances H3K4me3 in heat shocked animals lacking sams-1 , however, sams-1 cannot compensate for sams-4 , which is required to survive heat stress. This suggests that the regulatory functions of SAM depend on its enzymatic source and that provisioning of SAM may be an important regulatory step linking 1 CC function to phenotypes in aging and stress.
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eLife assessment
The manuscript proposes a mechanism by which different S-adenosylmethionine (SAM) synthase enzymes exhibit specificity towards target sequences, thereby proposing a novel layer of control over H3K4 trimethylation (H3K4me3). Such specificity is demonstrated in the context of responses to heat stress for two Caenorhabditis elegans SAM synthase enzymes, supporting the existence and importance of this novel mechanism of epigenetic control.
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Reviewer #1 (Public Review):
This study investigated the roles of sams-1 and sams-4, two enzymes that generate the major methyl donor SAM, in heat stress response and the associated molecular changes. The authors provided evidence that loss of sams-1 resulted in enhanced resistance to heat stress, whereas loss of sams-4 resulted in heightened sensitivity to heat stress. The authors further showed that whereas the basal level of the histone modification H3K4me3 in intestinal nuclei was substantially reduced in sams-1 loss-of-function mutants, H3K4me3 level greatly increased upon heat stress, and this increase depended on sams-4. Additional RNA-seq results revealed largely distinct heat stress-induced RNA expression changes in the sams-1 mutant and sams-4 knockdown worms. The authors further profiled genomic locations of H3K4me3 in sams-1 …
Reviewer #1 (Public Review):
This study investigated the roles of sams-1 and sams-4, two enzymes that generate the major methyl donor SAM, in heat stress response and the associated molecular changes. The authors provided evidence that loss of sams-1 resulted in enhanced resistance to heat stress, whereas loss of sams-4 resulted in heightened sensitivity to heat stress. The authors further showed that whereas the basal level of the histone modification H3K4me3 in intestinal nuclei was substantially reduced in sams-1 loss-of-function mutants, H3K4me3 level greatly increased upon heat stress, and this increase depended on sams-4. Additional RNA-seq results revealed largely distinct heat stress-induced RNA expression changes in the sams-1 mutant and sams-4 knockdown worms. The authors further profiled genomic locations of H3K4me3 in sams-1 mutant and sams-4 knockdown worms. Unfortunately, the lack of sufficient technical detail made it difficult to evaluate the H3K4me3 profiling data.
The paper provided several conceptual advances:
- Uncovering interesting and opposing heat stress phenotype associated with the loss of two related SAM synthases. Thus, even though both SAMS-1 and SAMS-4 produce SAM, the source of SAM production appears to have distinct consequences on the organismal heat stress response.
- Demonstration that SAMS-4 appeared able to compensate for the loss of SAMS-1 upon heat shock, resulting in restoration of the histone mark H3K4me3 in intestinal cells.
- Revealing largely different gene expression changes upon heat shock in animals lacking sams-1 or sams-4. Thus, the gene expression profiles corroborated the differential heat stress response.This paper describes one of the first adaptations of CUT&TAG in C. elegans, which can be of high impact on the field. Unfortunately, the lack of experimental detail made it difficult to evaluate the quality of the CUT&TAG data and the consequent interpretations.
Overall, the paper reported a number of interesting findings that will be of substantial interest to the field. However, the paper in its current form has substantial shortcomings, particularly related to the difficulty in evaluating the validity of H3K4me3 profiling data. The paper would also benefit from further discussion that attempts to reconcile some of the inconsistent results.
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Reviewer #2 (Public Review):
In this manuscript titled "S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress", the authors Godbole et al investigated how C. elegans SAM synthases, SAMS-1 and SAMS-4, affected gene expression, H3K4 trimethylation (H3K4me3), and the survival under heat stress. They found in this study that SAMS-4 was required for survival during heat shock. They reasoned that SAM supplied by SAMS-4 but not SAMS-1 might be responsible for generating H3K4me3 under heat shock and claimed that the two SAM synthases differentially affected histone methylation and thus gene expression in the heat shock response. This study suggested a stress-responsive mechanism by which the specific isozyme of SAM synthetase provided a specific pool of cellular SAM for H3K4me3. …
Reviewer #2 (Public Review):
In this manuscript titled "S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress", the authors Godbole et al investigated how C. elegans SAM synthases, SAMS-1 and SAMS-4, affected gene expression, H3K4 trimethylation (H3K4me3), and the survival under heat stress. They found in this study that SAMS-4 was required for survival during heat shock. They reasoned that SAM supplied by SAMS-4 but not SAMS-1 might be responsible for generating H3K4me3 under heat shock and claimed that the two SAM synthases differentially affected histone methylation and thus gene expression in the heat shock response. This study suggested a stress-responsive mechanism by which the specific isozyme of SAM synthetase provided a specific pool of cellular SAM for H3K4me3. Overall, this study is interesting but descriptive. Lacking necessary controls and mechanistic details weakened the significance of this work.
Strengths: Very interesting survival phenotypes in the loss of different SAM synthetases; technical success in CUT&tag in C. elegans.
Weaknesses: No clear conclusion can be drawn about whether and how SAM synthetases affect H3K4me3.
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Reviewer #3 (Public Review):
The manuscript " S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress " by Godbole et al proposes a novel mechanism by which different S-adenosylmethionine (SAM) synthase enzymes exhibit specificity towards target sequences, thereby providing a layer of control over H3K4 trimethylation (H3K4me3) in Caenorhabditis elegans. The authors detail an extensive investigation of the function of two C. elegans SAM synthase enzymes, SAMS-1 and SAMS-4. They provide evidence that mutation or knockdown of these two enzymes affected gene expression of distinct gene sets and that loss of these enzymes has opposite effects on survival under heat stress. These differential effects are linked to differential effects on histone modification H3K4me3 of specific …
Reviewer #3 (Public Review):
The manuscript " S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress " by Godbole et al proposes a novel mechanism by which different S-adenosylmethionine (SAM) synthase enzymes exhibit specificity towards target sequences, thereby providing a layer of control over H3K4 trimethylation (H3K4me3) in Caenorhabditis elegans. The authors detail an extensive investigation of the function of two C. elegans SAM synthase enzymes, SAMS-1 and SAMS-4. They provide evidence that mutation or knockdown of these two enzymes affected gene expression of distinct gene sets and that loss of these enzymes has opposite effects on survival under heat stress. These differential effects are linked to differential effects on histone modification H3K4me3 of specific target gene sets. It is unclear from this work how exactly this specificity may be achieved and some of the data regarding the role of other components of the methylation machinery are somewhat superficial and confusing. Nevertheless, the study suggested a novel mechanism by which H3K4me3 of specific gene sets may be controlled and this mechanism is novel and potentially important.
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