Our Team

  • Dr Jean-Michel Fustin

    Future Leaders Fellow

    +44 (0)161 306 7589

    Jean-Michel.Fustin@Manchester.ac.uk

  • Dr Benjamin Saer

    Senior Research Technician

    +44 (0)161 305 5264

    Ben.Saer@Manchester.ac.uk

  • Ms Jess Treeby

    PhD student (1st year)



  • Ms Milla Volic

    Biological Sciences BSc UG project

    2024 Prize for Top Molecular and Cell Biology Project

    2024 Prize for Top Medical Biochemistry Student

    Alumnus

  • Ms Feifan Shi

    MSc Clinical Biochemistry

    Alumnus





  • Ms Sophie Maddock

    MSc Clinical Biochemistry

    Alumnus





Our Research
Methyl Groups and Circadian Rhythms

At the Meth Lab, we focus on methyl metabolism, and more precisely how methyl metabolism interacts with our biological clock. Biological methylation of nucleic acids, proteins, fatty acids and small molecules are catalysed by methyltransferases that use the methyl donor co-substrate S-adenosylmethionine (SAM), synthesised by a universal metabolic pathway called the methyl cycle.

The synthesis of SAM requires the essential nutrients methionine, vitamin B9, B12 and choline. While the role of histone methylation in the function of our biological clock is relatively well understood, there are many more methylations whose physiological roles are uncertain, including RNA methylation and non-histone protein methylation.

We study the function of selected methylated nucleotides in messenger RNA, and we seek to define how SAM availability regulates general cellular methylations. We use molecular and behavioural circadian rhythms, which depend on transcription-translation feedback loops, as a read-out for the effects of genetic, dietary and pharmacological methylation deficiencies.

Our main research questions are:

  • 1 How do 1-C donors in the diet regulate our behaviour?
  • 2 How do mRNA methyltransferases regulate our behaviour?
  • 3 What are the key enzymes linking the circadian clock with 1-C metabolism?
  • 4 What is the circadian fate of dietary 1-C donours?

 

Recent Publications
  • Improved CaP Nanoparticles for Nucleic Acid and Protein Delivery to Neural Primary Cultures and Stem Cells

    Efficiently delivering exogenous materials into primary neurons and neural stem cells (NSCs) has long been a challenge in neurobiology. Existing methods have struggled with complex protocols, unreliable reproducibility, high immunogenicity, and cytotoxicity, causing a huge conundrum and hindering in-depth analyses. Here, we establish a cutting-edge method for transfecting primary neurons and NSCs, named teleofection, by a two-step process to enhance the formation of biocompatible calcium phosphate (CaP) nanoparticles. Teleofection enables both nucleic acid and protein transfection into primary neurons and NSCs, eliminating the need for specialized skills and equipment. It can easily fine-tune transfection efficiency by adjusting the incubation time and nanoparticle quantity, catering to various experimental requirements. Teleofection’s versatility allows for the delivery of different cargos into the same cell culture, whether simultaneously or sequentially. This flexibility proves invaluable for long-term studies, enabling the monitoring of neural development and synapse plasticity. Moreover, teleofection ensures the consistent and robust expression of delivered genes, facilitating molecular and biochemical investigations. Teleofection represents a significant advancement in neurobiology, which has promise to transcend the limitations of current gene delivery methods. It offers a user-friendly, cost-effective, and reproducible approach for researchers, potentially revolutionizing our understanding of brain function and development.

  • Dietary methionine/choline deficiency affects behavioural and molecular circadian rhythms.

    The feeding/fasting cycles controlled by our circadian clock impose great daily metabolic and physiological changes, and yet investigations into the consequences of metabolic deficiencies, either dietary or genetic, have often ignored the time of day or the circadian time of the animals or subjects. In addition, these deficiencies may themselves disrupt our circadian clock, causing secondary metabolic, physiological and behavioural disorders. Dietary methionine/choline deficiency in rodents is a common model for human non-alcoholic steatohepatitis, but methionine and choline are nutrients essential for many other processes beyond fatty acid synthesis in the liver, including biological methylations and 1-carbon metabolism, regulation of translation notably via the mTOR pathway, phospholipid synthesis, polyamine pathway and glutathione synthesis. We have previously shown that circadian rhythms in many organisms are highly sensitive to deficiency or excesses of 1-carbon metabolites. Using a methionine/choline deficient diet in mice, we illustrate the nutrigenomic crosstalk between circadian rhythms and 1-carbon metabolism. We show not only that circadian locomotor activity behaviour is profoundly, rapidly and reversibly affected by methionine/choline deficiency, but also that the effects of methionine/choline deficiency on gene expression and 1-carbon metabolites are dependent on circadian time, illustrating the importance of considering circadian rhythms in metabolic studies. This study also highlights the impact of what we eat, or don't, on our behaviour and biological rhythms.

  • Timed exercise stabilizes behavioral rhythms but not molecular programs in the brain’s suprachiasmatic clock.

    Timed daily access to a running-wheel (scheduled voluntary exercise; SVE) synchronizes rodent circadian rhythms and promotes stable, 24h rhythms in animals with genetically targeted impairment of neuropeptide signaling (Vipr2−/− mice). Here we used RNA-seq and/or qRT-PCR to assess how this neuropeptide signaling impairment as well as SVE shapes molecular programs in the brain clock (suprachiasmatic nuclei; SCN) and peripheral tissues (liver and lung). Compared to Vipr2+/+ animals, the SCN transcriptome of Vipr2−/− mice showed extensive dysregulation which included core clock components, transcription factors, and neurochemicals. Furthermore, although SVE stabilized behavioral rhythms in these animals, the SCN transcriptome remained dysregulated. The molecular programs in the lung and liver of Vipr2−/− mice were partially intact, although their response to SVE differed to that of these peripheral tissues in the Vipr2+/+ mice. These findings highlight that SVE can correct behavioral abnormalities in circadian rhythms without causing large scale alterations to the SCN transcriptome.

  • Methyl Metabolism and the Clock: An Ancient Story With New Perspectives.

    Methylation, that is, the transfer or synthesis of a -CH3 group onto a target molecule, is a pervasive biochemical modification found in organisms from bacteria to humans. In mammals, a complex metabolic pathway powered by the essential nutrients vitamin B9 and B12, methionine and choline, synthesizes S-adenosylmethionine, the methyl donor in the methylation of nucleic acids, proteins, fatty acids, and small molecules by over 200 substrate-specific methyltransferases described so far in humans. Methylations not only play a key role in scenarios for the origin and evolution of life, but they remain essential for the development and physiology of organisms alive today, and methylation deficiencies contribute to the etiology of many pathologies. The methylation of histones and DNA is important for circadian rhythms in many organisms, and global inhibition of methyl metabolism similarly affects biological rhythms in prokaryotes and eukaryotes. These observations, together with various pieces of evidence scattered in the literature on circadian gene expression and metabolism, indicate a close mutual interdependence between biological rhythms and methyl metabolism that may originate from prebiotic chemistry. This perspective first proposes an abiogenetic scenario for rhythmic methylations and then outlines mammalian methyl metabolism, before reanalyzing previously published data to draw a tentative map of its profound connections with the circadian clock.

  • Excess S-adenosylmethionine inhibits methylation via catabolism to adenine.

    The global dietary supplement market is valued at over USD 100 billion. One popular dietary supplement, S-adenosylmethionine, is marketed to improve joints, liver health and emotional well-being in the US since 1999, and has been a prescription drug in Europe to treat depression and arthritis since 1975, but recent studies questioned its efficacy. In our body, S-adenosylmethionine is critical for the methylation of nucleic acids, proteins and many other targets. The marketing of SAM implies that more S-adenosylmethionine is better since it would stimulate methylations and improve health. Previously, we have shown that methylation reactions regulate biological rhythms in many organisms. Here, using biological rhythms to assess the effects of exogenous S-adenosylmethionine, we reveal that excess S-adenosylmethionine disrupts rhythms and, rather than promoting methylation, is catabolized to adenine and methylthioadenosine, toxic methylation inhibitors. These findings further our understanding of methyl metabolism and question the safety of S-adenosylmethionine as a supplement.

  • Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver.

    Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells.

  • S-adenosyl-L-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling

    Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)–dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.

  • Methylation deficiency disrupts biological rhythms from bacteria to humans.

    The methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular physiology. We have previously shown that methyl cycle inhibition in mammals strongly affects circadian rhythms. Since the methyl cycle and circadian clocks have evolved early during evolution and operate in organisms across the tree of life, we sought to determine whether the link between the two is also conserved. Here, we show that methyl cycle inhibition affects biological rhythms in species ranging from unicellular algae to humans, separated by more than 1 billion years of evolution. In contrast, the cyanobacterial clock is resistant to methyl cycle inhibition, although we demonstrate that methylations themselves regulate circadian rhythms in this organism. Mammalian cells with a rewired bacteria-like methyl cycle are protected, like cyanobacteria, from methyl cycle inhibition, providing interesting new possibilities for the treatment of methylation deficiencies.

 

See full publication record (Pubmed)

 

Media Coverages
Symposiums and Seminars
Winter Symposium 2024

Our latest Symposium to date was dramatically hit by an early morning snow, but more than 50 attendees still braved the weather to make this event a success. Thank you Keystone Speaker Brendan for accepting our invitation!

Speakers:

  • 1 Jafar Cain
  • 2 Emma Leacy
  • 3 Magdalena Grudzien
  • 4 Felicity Hunter
  • 5 Rebecca Grossman
  • 6 Isaiah Ting
  • 7 Natalie Rogers
  • 8 Catherine Drysdale
  • 9 Frederick Odun-Ayo
  • 10 Dr Brendan Gabriel
  • 11 Aneglique Lamaza (online)
  • 12 Pierluigi Cocco (cancelled)
  • 13 Adam Liddle (cancelled)
PROMETHEUS Seminar Series

We are happy to introduce the PROMETHEUS Seminar Series with our first speaker from The University of Melbourne!

Speaker:

  • 1 Ms Jana Zeilinski
Summer Symposium 2022

Together with Prof Julie Gibbs and Ms Lorna Tittle we organised the Summer Symposium 2022 of the Centre for Biological Timing. This was the first 100% in person event at our Centre since the pandemic. Thank you to our Keystone speaker Jane for having accepted our invitation!

Speakers:

  • 1 Dr Rose Richardson
  • 2 Dr Altug Didikoglu
  • 3 Dr John Blaikley
  • 4 Dr Mino Belle
  • 5 Dr Michal Dudek
  • 6 Dr Laura Campbell
  • 7 Prof Jane McKeating
  • 8 Dr Robert Maidstone
  • 9 Dr Joan Chang
  • 10 Dr Jean-Michel Fustin
Winter Symposium 2022

The first CfBT Winter Symposium was held on Tuesday 1st February 2022, as a full day hybrid event, with attendance available both in person and online. The event focused on presentations by PhD students. Professor Maria Robles from the Institute of Medical Psychology at LMU Munich gave a keynote presentation on “Proteomics around the clock”. Thank you Maria!

An online poll was run for the duration of the event, so that attendees could choose their favourite presentations. The top three speakers were awarded a 30£ Amazon voucher and certificate at the end of the day. Awardees were: Helene Borrmann, David McManus and Ruby Chrisp.

Speakers:

  • 1 Helene Borrmann
  • 2 Florian Zirpel
  • 3 Shiyang Li
  • 4 Namrata Chowdhury
  • 5 Nicola Smyllie
  • 6 Alex Koch
  • 7 Ruby Chrisp
  • 8 Akanksha Bafna
  • 9 Prof Maria Robles
  • 10 Patrycja anna Orlowska- Feuer
  • 11 David McManus
  • 12 Joshua Burton
  • 13 Aghileh Ebrahimi
  • 14 Tom Butler
  • 15 Edward Hayter
  • 16 Elizabeth Tamayo
  • 17 Karolina Krakowiak
Summer Showcase 2021

The CfBT is the largest biological timing research community in Europe, with 27 principal investigators, 86 research staff, and 41 graduate students. Led by Professor Robert Lucas, the CFBT brings together world-leading researchers with a multidisciplinary approach to cellular timers and circadian clocks. Our research spans from model organisms and understanding of fundamental cellular events, through to clinical intervention into human diseases. We undertake this research across three major research themes which were showcased across three afternoons of talks. Thank you very much to the external speakers Henrik, Masao and Katja for responding to our invitation!

Speakers:

  • 1 Martin Rutter
  • 2 Louise Hunter
  • 3 Hannah Durrington
  • 4 Henrik Oster
  • 5 Tim Brown
  • 6 Nina Milosavljevic
  • 7 Masao Doi
  • 8 David Bechtold
  • 9 Qin-Jun Meng
  • 10 Katja Lamia
Grants
News
Jess presents her first poster at the International Chronobiology Summer School 2024   

Jess goes to Nagoya between August 5-8 2024 to present her first poster titled "HEPATIC GENE EXPRESSION IN RESPONSE TO FASTING IS SEX-DEPENDENT."

Jess just received a travel grant! Congratulations! Thank you very much for this, Yoshimura sensei and Shigeyoshi sensei!

5-8/08/2024 

Ms Milla Volic awarded two Graduation Prizes   

Milla was awarded two prizes: for top molecular and cell project and for top medical biochemistry student? Congratulations, Milla!

11/07/2024 

New preprint out!   

We have published our new preprint titled "Dietary methionine/choline deficiency affects behavioural and molecular circadian rhythms."

04/01/2024 

Wellcome's Multi–omics in Metabolic Disease conference

On Wednesday 7th-9th of June 2023, Ben & I presented a poster at the Wellcome's Multi–omics in Metabolic Disease conference. We had a great time! The full programme with abstracts can be downloaded here. You can view our poster by clicking on the image to the right.

10/06/2023