PT  - JOURNAL ARTICLE
AU  - Kristina Reinmets
AU  - Johanna Bischof
AU  - Emily Taketa
AU  - Michael Levin
AU  - Stephen M. Fuchs
TI  - S-adenosylhomocysteine hydrolase regulates anterior patterning in <em>Dugesia japonica</em>
AID  - 10.1101/2020.01.22.916072
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.22.916072
4099  - http://biorxiv.org/content/early/2020/01/23/2020.01.22.916072.short
4100  - http://biorxiv.org/content/early/2020/01/23/2020.01.22.916072.full
AB  - Background Biological methylation requires S-adenosylmethionine (SAM) and participates in a range of processes from modulation of gene expression via histone modifications to neurotransmitter synthesis. An important factor in all methylation reactions is the concentration ratio of SAM to methylation byproduct S-adenosylhomocysteine (SAH). SAH hydrolase, also known as adenosylhomocysteinase, depletes SAH and thereby facilitates metabolite recycling and maintains the methylation permissive SAM/SAH ratio. While the importance of SAH hydrolase in sustaining methylation is obvious on the cellular level, the function of this metabolic process on the organismal scale is not clear.Results We used planarian Dugesia japonica to investigate the role SAH hydrolase in physiological homeostasis on the body-wide scale. Remarkably, pharmacological inhibition of the SAH hydrolase results in regression of anterior tissues and is accompanied by extensive apoptosis throughout the planarian body. Moreover, exposure to the SAHH inhibitor AdOx leads to changes in brain morphology and spatial shift in the expression of Wnt-modulator Notum. Strikingly, planarians are able to overcome these destructive patterning defects through regeneration of the anterior tissues and adaptation to the used inhibitor. Transcriptome analysis indicates that resistance to the SAHH inhibitor is at least partly mediated by changes in folate cycle and lipid metabolism.Conclusions SAH hydrolase plays a critical role in planarian homeostasis and anterior patterning potentially through modulation of Wnt signaling. Moreover, planarian adaptation to the SAHH inhibitor via metabolic reprogramming suggests potential targets for addressing methylation-related human conditions.