Home Biology Metabolic sinkholes: Histones as methyl repositories

Metabolic sinkholes: Histones as methyl repositories

Metabolic sinkholes: Histones as methyl repositories


Quotation: Karimian A, Vogelauer M, Kurdistani SK (2023) Metabolic sinkholes: Histones as methyl repositories. PLoS Biol 21(10):


Printed: October 27, 2023

Copyright: © 2023 Karimian et al. That is an open entry article distributed underneath the phrases of the Inventive Commons Attribution License, which allows unrestricted use, distribution, and replica in any medium, offered the unique creator and supply are credited.

Funding: A.S., M.V. and S.Ok.Ok. are supported by the Nationwide Institutes of Well being grant GM140106, and the Moore-Simons Challenge on the Origin of the Eukaryotic Cell award 9740 to S.Ok.Ok. The funders had no position in research design, knowledge assortment and evaluation, choice to publish, or preparation of the manuscript.

Competing pursuits: The authors have declared that no competing pursuits exist.

S-adenosylmethionine (SAM) features as the most important methyl donor for quite a few mobile reactions and processes together with DNA, RNA and protein methylation, amino acid metabolism, nucleotide synthesis, neurotransmitter synthesis, and extra. SAM’s position is facilitated by its available methyl group (CH3) for switch in numerous methylation reactions catalysed by methyltransferase enzymes [1].

The utilization of SAM by methyltransferases generates the by-product S-adenosylhomocysteine (SAH). SAH competes with SAM for binding to methyltransferase enzymes and may inhibit the enzyme’s skill to hold out additional methylation reactions. SAH itself can endure additional metabolism: it may be recycled by way of the methionine cycle to regenerate SAM or directed into the transsulfuration pathway, supporting the synthesis of sulfur-containing compounds corresponding to cysteine and glutathione (Fig 1) [1]. Consequently, the SAM/SAH ratio is a vital parameter that displays the mobile capability for methylation reactions in addition to the metabolic pathways reliant on SAH.


Fig 1. Histones as sinks for methyl teams and their interaction with different methyl sinks.

Within the methionine cycle, SAM conversion to SAH is contingent on the presence of methyl acceptors, sometimes called methyl sinks. SAH may be additional metabolized by way of the transsulfuration pathway, contributing to the synthesis of important sulfur-containing molecules corresponding to cysteine and glutathione. Cells can methylate numerous substrates to function methyl sinks. Amongst these reactions, an inverse relationship exists between HMTs and NNMT, which generates 1MNA, in most cancers cells, in addition to between HMTs and PEMT, which generates PC, in regular cells. This implies that histone methylation by HMTs may be employed instead technique to keep up an applicable SAM/SAH ratio when NNMT or PEMT actions are low in most cancers and regular cells, respectively. The selection of which pathway to make the most of could also be influenced by elements together with the capability and limitations of every methyl sink, the downstream features of the methylated response merchandise, the destiny of the methyl group itself, and the following metabolism of SAH. Importantly, adjustments in histone methylation in response to methyl sink utilization don’t seem to correlate with alterations within the expression of genes sometimes related to histone methylation. THF–tetrahydrofolate; R and R’ = fatty acids.


Balancing the SAM/SAH ratio hinges partly on substrates able to accepting SAM’s methyl group, generally known as “methylation sinks” (Fig 1). Notable reactions that contain SAM utilization and lead to its diminished ranges embody the synthesis of 1-methylnicotinamide (1MNA) from nicotinamide (NA) through nicotinamide N-methyltransferase (NNMT), and the conversion of phosphatidylethanolamine (PE) into phosphatidylcholine (PC) by phosphatidylethanolamine methyltransferase (PEMT) [2].

Histones, boasting quite a few lysine residues vulnerable to methylation and an array of histone methyltransferases (HMTs), have been demonstrated as methyl sinks in budding yeast, significantly underneath circumstances of impaired phospholipid methylation [3]. Nonetheless, the query of whether or not histones fulfill a comparable position in different eukaryotes, together with human cells, remained unanswered.

On this problem, Perez and Sarkies [4] adeptly leverage a considerable physique of revealed knowledge to exhibit that histones certainly perform as different methyl sinks to NA and PE in human cells (Fig 1). Their first key perception got here from correlating the expression of HMTs with metabolite ranges in most cancers datasets. This evaluation unveiled 1MNA as probably the most negatively correlated metabolite with the expression of most HMTs, with an analogous inverse correlation noticed between HMTs and NNMT, the enzyme that generates 1MNA.

These reciprocal relationships turned stronger when aggregating the expression of all HMTs, suggesting that every HMT contributes to the overarching inverse relationship no matter its recognized affiliation with gene expression or repression. In step with this, the expression of HMTs confirmed a optimistic correlation amongst themselves, suggesting potential coordination of their total expression which may be linked to the actions of different methyl sink pathways.

In datasets from regular tissues, the expression of HMTs exhibited a weaker unfavorable correlation with NNMT however a stronger one with PEMT. As soon as once more, the mixture expression of HMTs displayed the strongest inverse relationship with PEMT, suggesting the coordinate exercise of HMTs because the pivotal issue. Nonetheless, there was some overlap noticed. Some cancers displayed unfavorable correlations between HMTs and PEMTs, whereas sure regular tissues exhibited unfavorable correlations between HMTs and NNMTs.

These findings recommend that totally different cells and tissues, maybe relying on metabolic or physiologic contexts, might depend on NNMT or PEMT to scale back SAM ranges and on histone methylation exercise instead technique when NNMT or PEMT expression is low (Fig 1). In keeping with this, the authors noticed that genome-wide histone methylation ranges on most lysine residues in histones H3 or H4 are additionally inversely associated to NNMT or PEMT expression, albeit with some exceptions which may be attributed to different roles of histone methylation in particular cell varieties.

Remarkably, the presence of both excessive ranges of histone methylation or NNMT/PEMT (indicating low ranges of histone methylation) didn’t correlate with adjustments within the transcription of genes related to histone methylation. This implies that the general stage of histone methylation is extra indicative of the equilibrium between the actions of various methyl sink pathways relatively than gene expression.

After noting the shocking coordinated expression of HMTs within the human datasets, the authors turned to knowledge from the worm Caenorhabditis elegans to discover potential mechanisms governing the co-regulation of HMTs. They found intriguing proof suggesting that HMTs may be topic to coordinated regulation by the Retinoblastoma protein (Rb) and E2F transcription elements, well-known regulators of the cell cycle [5]. Persistently, the promoters of human HMT genes have been discovered to be enriched with E2F1 transcription issue binding websites. This potential regulation of HMTs by the Rb/E2F axis additionally establishes a hyperlink between SAM/SAH ratio, HMT actions, and cell cycle development.

Moreover, this evaluation allowed the authors to suggest a mannequin for a way the inverse relationship between HMTs and NNMT could also be achieved. Their analyses steered that the Rb/E2F exercise maintains the suppression of HMTs, which, in flip, probably suppress NNMT expression. Consequently, when HMT actions, and thus histone methylation, are engaged, the NNMT pathway is down-regulated, thereby guaranteeing reciprocal actions of those 2 methyl sink pathways. Though the regulation of HMTs might differ throughout numerous organisms, histones functioning as a metabolic sink for methyl teams could also be a standard phenomenon in eukaryotes.

With the presence of assorted methyl group sinks, an vital query arises: What elements or circumstances decide the preferential utilization of 1 sink pathway over one other? Whereas the reply will not be recognized, it might lie within the capability and limitations of every methyl sink, the downstream features of the methylated response merchandise together with the methyl group itself in addition to the following metabolism of SAH.

As an illustration, it’s conceivable that the manufacturing of SAH as a selected consequence of histone methylation might gas syntheses of cysteine and glutathione, that are vital for extremely proliferative cells corresponding to most cancers cells [6]. Supporting this notion is the optimistic correlation of HMT expression and cystathionine, a precursor metabolite to cysteine and glutathione. Doubtlessly associated to this, a latest research demonstrated that impairing the perform of the SWI/SNF chromatin reworking complicated induces a cysteine-deficient phenotype [7]. Taken collectively, these findings recommend that histones might play a direct position in regulating sulfur homeostasis.

Growing proof means that chromatin features as a metabolic organelle. It not solely receives alerts from the cell, within the type of small molecules that modify histones for instance, but additionally offers instructive alerts again to control mobile metabolism and physiology. Chromatin might function a reservoir of acetate [8,9], a repository of methyl teams [3,4], or supply of cuprous (Cu1+) ions, the latter facilitated by the copper reductase exercise of histone H3 [10]. These features seemingly function independently of standard transcriptional regulation. Actually, the noticed adjustments in gene exercise might characterize adaptive responses geared toward implementing and managing the metabolic features of chromatin. This metabolic perspective on histones and chromatin prompts a reevaluation of their roles in biology and illness.



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