Publications

The Babraham Institute Publications database contains details of all publications resulting from our research groups and scientific services.

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Title / Authors / Details Open Access Download

MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer.
Casciano JC, Perry C, Cohen-Nowak AJ, Miller KD, Vande Voorde J, Zhang Q, Chalmers S, Sandison ME, Liu Q, Hedley A, McBryan T, Tang HY, Gorman N, Beer T, Speicher DW, Adams PD, Liu X, Schlegel R, McCarron JG, Wakelam MJO, Gottlieb E, Kossenkov AV, Schug ZT

Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood.

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British journal of cancer, 1, 1,

PMID: 31942031

The genetic landscape of Arab Population, Chechens and Circassians subpopulations from Jordan through HV1 and HV2 regions of mtDNA.
Al-Eitan L, Saadeh H, Alnaamneh A, Darabseh S, Al-Sarhan N, Alzihlif M, Hakooz N, Ivanova E, Kelsey G, Dajani R

Mitochondrial DNA (mtDNA) is widely used in several fields including medical genetics, forensic science, genetic genealogy, and evolutionary anthropology. In this study, mtDNA haplotype diversity was determined for 293 unrelated subjects from Jordanian population (Circassians, Chechens, and the original inhabitants of Jordan). A total of 102 haplotypes were identified and analyzed among the populations to describe the maternal lineage landscape. Our results revealed that the distribution of mtDNA haplotype frequencies among the three populations showed disparity and significant differences when compared to each other. We also constructed mitochondrial haplotype classification trees for the three populations to determine the phylogenetic relationship of mtDNA haplotype variants, and we observed clear differences in the distribution of maternal genetic ancestries, especially between Arab and the minority ethnic populations. To our knowledge, this study is the first, to date, to characterize mitochondrial haplotypes and haplotype distributions in a population-based sample from the Jordanian population. It provides a powerful reference for future studies investigating the contribution of mtDNA variation to human health and disease and studying population history and evolution by comparing the mtDNA haplotypes to other populations.

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Gene, 729, 1,

PMID: 31884104

Genome-wide assessment of DNA methylation in mouse oocytes reveals effects associated with in vitro growth, superovulation, and sexual maturity.
Saenz-de-Juano MD, Ivanova E, Billooye K, Herta AC, Smitz J, Kelsey G, Anckaert E

In vitro follicle culture (IFC), as applied in the mouse system, allows the growth and maturation of a large number of immature preantral follicles to become mature and competent oocytes. In the human oncofertility clinic, there is increasing interest in developing this technique as an alternative to ovarian cortical tissue transplantation and to preserve the fertility of prepubertal cancer patients. However, the effect of IFC and hormonal stimulation on DNA methylation in the oocyte is not fully known, and there is legitimate concern over epigenetic abnormalities that could be induced by procedures applied during assisted reproductive technology (ART).

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Clinical epigenetics, 11, 1,

PMID: 31856890

A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation.
Demond H, Anvar Z, Jahromi BN, Sparago A, Verma A, Davari M, Calzari L, Russo S, Jahromi MA, Monk D, Andrews S, Riccio A, Kelsey G

Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses: in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. The rarity of these disorders and the possibility that methylation defects originate in oocytes have made these questions very challenging to address.

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Genome medicine, 11, 1,

PMID: 31847873

Open Access

Novel HDAC6 Inhibitors Increase Tubulin Acetylation and Rescue Axonal Transport of Mitochondria in a Model of Charcot-Marie-Tooth Type 2F.
Adalbert R, Kaieda A, Antoniou C, Loreto A, Yang X, Gilley J, Hoshino T, Uga K, Makhija MT, Coleman MP

Disruption of axonal transport causes a number of rare, inherited axonopathies and is heavily implicated in a wide range of more common neurodegenerative disorders, many of them age-related. Acetylation of α-tubulin is one important regulatory mechanism, influencing microtubule stability and motor protein attachment. Of several strategies so far used to enhance axonal transport, increasing microtubule acetylation through inhibition of the deacetylase enzyme histone deacetylase 6 (HDAC6) has been one of the most effective. Several inhibitors have been developed and tested in animal and cellular models, but better drug candidates are still needed. Here we report the development and characterization of two highly potent HDAC6 inhibitors, which show low toxicity, promising pharmacokinetic properties, and enhance microtubule acetylation in the nanomolar range. We demonstrate their capacity to rescue axonal transport of mitochondria in a primary neuronal culture model of the inherited axonopathy Charcot-Marie-Tooth Type 2F, caused by a dominantly acting mutation in heat shock protein beta 1.

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ACS chemical neuroscience, 1, 1,

PMID: 31845794

Cyt-Geist: Current and Future Challenges in Cytometry: Reports of the CYTO 2019 Conference Workshops.
Czechowska K, Lannigan J, Aghaeepour N, Back JB, Begum J, Behbehani G, Bispo C, Bitoun D, Fernández AB, Boova ST, Brinkman RR, Ciccolella CO, Cotleur B, Davies D, Dela Cruz GV, Del Rio-Guerra R, Des Lauriers-Cox AM, Douagi I, Dumrese C, Bonilla Escobar DL, Estevam J, Ewald C, Fossum A, Gaudillière B, Green C, Groves C, Hall C, Haque Y, Hedrick MN, Hogg K, Hsieh EWY, Irish J, Lederer J, Leipold M, Lewis-Tuffin LJ, Litwin V, Lopez P, Nasdala I, Nedbal J, Ohlsson-Wilhelm BM, Price KM, Rahman AH, Rayanki R, Rieger AM, Robinson JP, Shapiro H, Sun YS, Tang VA, Tesfa L, Telford WG, Walker R, Welsh JA, Wheeler P, Tárnok A

See publication

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Cytometry. Part A : the journal of the International Society for Analytical Cytology, 95, 12,

PMID: 31833655

Mammalian phospholipase D: Function, and therapeutics.
McDermott MI, Wang Y, Wakelam MJO, Bankaitis VA

Despite being discovered over 60 years ago, the precise role of Phospholipase D (PLD) is still being elucidated. PLD enzymes catalyze the hydrolysis of the phosphodiester bond of glycerophospholipids producing phosphatidic acid and the free headgroup. PLD family members are found in organisms ranging from viruses, and bacteria to plants, and mammals, and they display a range of substrate specificities, are regulated by a diverse range of molecules, and have been implicated in a broad range of cellular processes including receptor signaling, cytoskeletal regulation and membrane trafficking. Recent technological advances including: the development of PLD knockout mice, isoform-specific antibodies, and specific inhibitors are finally permitting a thorough analysis of the in vivo role of mammalian PLDs. These studies are facilitating increased recognition of PLD's role in disease states including cancers and Alzheimer's disease, offering potential as a target for therapeutic intervention.

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Progress in lipid research, 0, 0,

PMID: 31830503

Multi-omics profiling of mouse gastrulation at single-cell resolution.
Argelaguet R, Clark SJ, Mohammed H, Stapel LC, Krueger C, Kapourani CA, Imaz-Rosshandler I, Lohoff T, Xiang Y, Hanna CW, Smallwood S, Ibarra-Soria X, Buettner F, Sanguinetti G, Xie W, Krueger F, Göttgens B, Rugg-Gunn PJ, Kelsey G, Dean W, Nichols J, Stegle O, Marioni JC, Reik W

Formation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan and is associated with major transcriptional changes. Global epigenetic reprogramming accompanies these changes, but the role of the epigenome in regulating early cell-fate choice remains unresolved, and the coordination between different molecular layers is unclear. Here we describe a single-cell multi-omics map of chromatin accessibility, DNA methylation and RNA expression during the onset of gastrulation in mouse embryos. The initial exit from pluripotency coincides with the establishment of a global repressive epigenetic landscape, followed by the emergence of lineage-specific epigenetic patterns during gastrulation. Notably, cells committed to mesoderm and endoderm undergo widespread coordinated epigenetic rearrangements at enhancer marks, driven by ten-eleven translocation (TET)-mediated demethylation and a concomitant increase of accessibility. By contrast, the methylation and accessibility landscape of ectodermal cells is already established in the early epiblast. Hence, regulatory elements associated with each germ layer are either epigenetically primed or remodelled before cell-fate decisions, providing the molecular framework for a hierarchical emergence of the primary germ layers.

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Nature, 576, 7787,

PMID: 31827285

Open Access

Azathioprine Has a Deleterious Effect on the Bone Health of Mice with DSS-Induced Inflammatory Bowel Disease.
Morgan S, Hooper KM, Milne EM, Farquharson C, Stevens C, Staines KA

Patients with inflammatory bowel disease (IBD) often present poor bone health and are 40% more at risk of bone fracture. Studies have implicated autophagy in IBD pathology and drugs used to treat IBD stimulate autophagy in varying degrees, however, their effect on the skeleton is currently unknown. Here, we have utilised the dextran sulphate sodium (DSS) model of colitis in mice to examine the effects of the thiopurine drug azathioprine on the skeleton. Ten-week-old male mice ( = 6/group) received 3.0% DSS in their drinking water for four days, followed by a 14-day recovery period. Mice were treated with 10 mg/kg/day azathioprine or vehicle control. Histopathological analysis of the colon from DSS mice revealed significant increases in scores for inflammation severity, extent, and crypt damage ( < 0.05). Azathioprine provided partial protection to the colon, as reflected by a lack of significant difference in crypt damage and tissue regeneration with DSS treatment. MicroCT of vehicle-treated DSS mice revealed azathioprine treatment had a significant detrimental effect on the trabecular bone microarchitecture, independent of DSS treatment. Specifically, significant decreases were observed in bone volume/tissue volume ( < 0.01), and trabecular number ( < 0.05), with a concurrent significant increase in trabecular pattern factor ( < 0.01). Immunohistochemical labelling for LC3 revealed azathioprine to induce autophagy in the bone marrow. Together these data suggest that azathioprine treatment may have a deleterious effect on IBD patients who may already be at increased risk of osteoporotic bone fractures and thus will inform on future treatment strategies for patient stratification.

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International journal of molecular sciences, 20, 23,

PMID: 31816823

Open Access

Transcription-induced formation of extrachromosomal DNA during yeast ageing.
Hull RM, King M, Pizza G, Krueger F, Vergara X, Houseley J

Extrachromosomal circular DNA (eccDNA) facilitates adaptive evolution by allowing rapid and extensive gene copy number variation and is implicated in the pathology of cancer and ageing. Here, we demonstrate that yeast aged under environmental copper accumulate high levels of eccDNA containing the copper-resistance gene CUP1. Transcription of the tandemly repeated CUP1 gene causes CUP1 eccDNA accumulation, which occurs in the absence of phenotypic selection. We have developed a sensitive and quantitative eccDNA sequencing pipeline that reveals CUP1 eccDNA accumulation on copper exposure to be exquisitely site specific, with no other detectable changes across the eccDNA complement. eccDNA forms de novo from the CUP1 locus through processing of DNA double-strand breaks (DSBs) by Sae2, Mre11 and Mus81, and genome-wide analyses show that other protein coding eccDNA species in aged yeast share a similar biogenesis pathway. Although abundant, we find that CUP1 eccDNA does not replicate efficiently, and high-copy numbers in aged cells arise through frequent formation events combined with asymmetric DNA segregation. The transcriptional stimulation of CUP1 eccDNA formation shows that age-linked genetic change varies with transcription pattern, resulting in gene copy number profiles tailored by environment.

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PLoS biology, 17, 12,

PMID: 31794573

Open Access

The application of cell surface markers to demarcate distinct human pluripotent states.
Goodwin J, Laslett AL, Rugg-Gunn PJ

Recent advances in human pluripotent stem cell (hPSC) research have uncovered different subpopulations within stem cell cultures and have captured a range of pluripotent states that hold distinct molecular and functional properties. At the two ends of the pluripotency spectrum are naïve and primed hPSC, whereby naïve hPSC grown in stringent conditions recapitulate features of the preimplantation human embryo, and the conventionally grown primed hPSC align closer to the early postimplantation embryo. Investigating these cell types will help to define the mechanisms that control early development and should provide new insights into stem cell properties such as cell identity, differentiation and reprogramming. Monitoring cell surface marker expression provides a valuable approach to resolve complex cell populations, to directly compare between cell types, and to isolate viable cells for functional experiments. This review discusses the discovery and applications of cell surface markers to study human pluripotent cell types with a particular focus on the transitions between naïve and primed states. Highlighted areas for future study include the potential functions for the identified cell surface proteins in pluripotency, the production of new high-quality monoclonal antibodies to naïve-specific protein epitopes and the use of cell surface markers to characterise subpopulations within pluripotent states.

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Experimental cell research, 0, 0,

PMID: 31790696

Open Access

The role and mechanisms of DNA methylation in the oocyte.
Sendžikaitė G, Kelsey G

Epigenetic information in the mammalian oocyte has the potential to be transmitted to the next generation and influence gene expression; this occurs naturally in the case of imprinted genes. Therefore, it is important to understand how epigenetic information is patterned during oocyte development and growth. Here, we review the current state of knowledge of de novo DNA methylation mechanisms in the oocyte: how a distinctive gene-body methylation pattern is created, and the extent to which the DNA methylation machinery reads chromatin states. Recent epigenomic studies building on advances in ultra-low input chromatin profiling methods, coupled with genetic studies, have started to allow a detailed interrogation of the interplay between DNA methylation establishment and chromatin states; however, a full mechanistic description awaits.

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Essays in biochemistry, 63, 6,

PMID: 31782490

Open Access

Protocols for Northern Analysis of Exosome Substrates and Other Noncoding RNAs.
Cruz C, Houseley J

Over the past decade a plethora of noncoding RNAs (ncRNAs) have been identified, initiating an explosion in RNA research. Although RNA sequencing methods provide unsurpassed insights into ncRNA distribution and expression, detailed information on structure and processing are harder to extract from sequence data. In contrast, northern blotting methods provide uniquely detailed insights into complex RNA populations but are rarely employed outside specialist RNA research groups. Such techniques are generally considered difficult for nonspecialists, which is unfortunate as substantial technical advances in the past few decades have solved the major challenges. Here we present simple, reproducible and highly robust protocols for separating glyoxylated RNA on agarose gels and heat denatured RNA on polyacrylamide-urea gels using standard laboratory electrophoresis equipment. We also provide reliable transfer and hybridization protocols that do not require optimization for most applications. Together, these should allow any molecular biology lab to elucidate the structure and processing of ncRNAs of interest.

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Methods in molecular biology (Clifton, N.J.), 2062, 1,

PMID: 31768973

Open Access

BNC1 regulates cell heterogeneity in human pluripotent stem cell-derived epicardium.
Gambardella L, McManus SA, Moignard V, Sebukhan D, Delaune A, Andrews S, Bernard WG, Morrison MA, Riley PR, Göttgens B, Gambardella Le Novère N, Sinha S

The murine developing epicardium heterogeneously expresses the transcription factors TCF21 and WT1. Here, we show that this cell heterogeneity is conserved in human epicardium, regulated by BNC1 and associated with cell fate and function. Single cell RNA sequencing of epicardium derived from human pluripotent stem cells (hPSC-epi) revealed that distinct epicardial subpopulations are defined by high levels of expression for the transcription factors BNC1 or TCF21. WT1 cells are included in the BNC1 population, which was confirmed in human foetal hearts. THY1 emerged as a membrane marker of the TCF21 population. We show that THY1 cells can differentiate into cardiac fibroblasts (CFs) and smooth muscle cells (SMCs), whereas THY1 cells were predominantly restricted to SMCs. Knocking down BNC1 during the establishment of the epicardial populations resulted in a homogeneous, predominantly TCF21 population. Network inference methods using transcriptomic data from the different cell lineages derived from the hPSC-epi delivered a core transcriptional network organised around WT1, TCF21 and BNC1. This study unveils a list of epicardial regulators and is a step towards engineering subpopulations of epicardial cells with selective biological activities.

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Development (Cambridge, England), 146, 24,

PMID: 31767620

Open Access

DNA methylation aging clocks: challenges and recommendations.
Bell CG, Lowe R, Adams PD, Baccarelli AA, Beck S, Bell JT, Christensen BC, Gladyshev VN, Heijmans BT, Horvath S, Ideker T, Issa JJ, Kelsey KT, Marioni RE, Reik W, Relton CL, Schalkwyk LC, Teschendorff AE, Wagner W, Zhang K, Rakyan VK

Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.

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Genome biology, 20, 1,

PMID: 31767039

Open Access

Dual-mechanism ERK1/2 inhibitors exploit a distinct binding mode to block phosphorylation and nuclear accumulation of ERK1/2.
Kidger AM, Munck JM, Saini HK, Balmanno K, Minihane E, Courtin A, Graham B, O'Reilly M, Odle R, Cook SJ

The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is frequently deregulated in cancer due to activating mutations of growth factor receptors, RAS or BRAF. Both RAF and MEK1/2 inhibitors are clinically approved and various ERK1/2 inhibitors (ERKi) are currently undergoing clinical trials. To date ERKi display two distinct mechanisms of action (MoA); catalytic ERKi solely inhibit ERK1/2 catalytic activity, whereas dual mechanism ERKi additionally prevent the activating phosphorylation of ERK1/2 at its T-E-Y motif by MEK1/2. These differences may impart significant differences in biological activity because T-E-Y phosphorylation is the signal for nuclear entry of ERK1/2, allowing them to access many key transcription factor targets. Here, we characterised the MoA of five ERKi and examined their functional consequences in terms of ERK1/2 signalling, gene expression and anti-proliferative efficacy. We demonstrate that catalytic ERKi promote a striking nuclear accumulation of p-ERK1/2 in KRAS mutant cell lines. In contrast, dual mechanism ERKi exploit a distinct binding mode to block ERK1/2 phosphorylation by MEK1/2, exhibit superior potency and prevent the nuclear accumulation of ERK1/2. Consequently, dual-mechanism ERKi exhibit more durable pathway inhibition and enhanced suppression of ERK1/2-dependent gene expression compared to catalytic ERKi, resulting in increased efficacy across BRAF and RAS mutant cell lines.

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Molecular cancer therapeutics, 1, 1,

PMID: 31748345

A nutritional memory effect counteracts benefits of dietary restriction in old mice.
Hahn O, Drews LF, Nguyen A, Tatsuta T, Gkioni L, Hendrich O, Zhang Q, Langer T, Pletcher S, Wakelam MJO, Beyer A, Grönke S, Partridge L

Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at old age remains elusive. Here, we report results of a late-life DR switch experiment employing 800 mice, in which 24 months old female mice were switched from ad libitum (AL) to DR or vice versa. Strikingly, the switch from DR-to-AL acutely increases mortality, whereas the switch from AL-to-DR causes only a weak and gradual increase in survival, suggesting a memory of earlier nutrition. RNA-seq profiling in liver, brown (BAT) and white adipose tissue (WAT) demonstrate a largely refractory transcriptional and metabolic response to DR after AL feeding in fat tissue, particularly in WAT, and a proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Our results provide evidence for a nutritional memory as a limiting factor for DR-induced longevity and metabolic remodeling of WAT in mammals.

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Nature metabolism, 1, 11,

PMID: 31742247

Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration.
Loreto A, Hill CS, Hewitt VL, Orsomando G, Angeletti C, Gilley J, Lucci C, Sanchez-Martinez A, Whitworth AJ, Conforti L, Dajas-Bailador F, Coleman MP

Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLD and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.

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Neurobiology of disease, 134, 1,

PMID: 31740269

An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis.
Odle RI, Walker SA, Oxley D, Kidger AM, Balmanno K, Gilley R, Okkenhaug H, Florey O, Ktistakis NT, Cook SJ

Since nuclear envelope breakdown occurs during mitosis in metazoan cells, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. However, repression of macroautophagy during mitosis remains controversial and mechanistic detail limited to the suggestion that CDK1 phosphorylates VPS34. Here, we show that initiation of macroautophagy, measured by the translocation of the ULK complex to autophagic puncta, is repressed during mitosis, even when mTORC1 is inhibited. Indeed, mTORC1 is inactive during mitosis, reflecting its failure to localize to lysosomes due to CDK1-dependent RAPTOR phosphorylation. While mTORC1 normally represses autophagy via phosphorylation of ULK1, ATG13, ATG14, and TFEB, we show that the mitotic phosphorylation of these autophagy regulators, including at known repressive sites, is dependent on CDK1 but independent of mTOR. Thus, CDK1 substitutes for inhibited mTORC1 as the master regulator of macroautophagy during mitosis, uncoupling autophagy regulation from nutrient status to ensure repression of macroautophagy during mitosis.

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Molecular cell, S1097-2765, 19,

PMID: 31733992

Open Access

Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.
Sale MJ, Minihane E, Monks NR, Gilley R, Richards FM, Schifferli KP, Andersen CL, Davies EJ, Vicente MA, Ozono E, Markovets A, Dry JR, Drew L, Flemington V, Proia T, Jodrell DI, Smith PD, Cook SJ

BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-X inhibitors is stronger in CRC, correlating with a low MCL1:BCL-X ratio; indeed the MCL1:BCL-X ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-X inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.

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Nature communications, 10, 1,

PMID: 31727888

Open Access

Autophagosome biogenesis machinery.
Walker SA, Ktistakis NT

We review current knowledge of the process of autophagosome formation with special emphasis on the very early steps: turning on the autophagy pathway, assembling the autophagy machinery, and building the autophagosome. The pathway is remarkably well co-ordinated spatially and temporally, and it shows broad conservation across species and cell types, including neurons. In addition, although much current knowledge derives mostly from settings of non-selective autophagy, recent work also indicates that selective autophagy, and more specifically mitophagy, shows similar dynamics. Having an understanding of this remarkable process may help the design of novel therapeutics for neurodegeneration and other pathologies.

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Journal of molecular biology, 1089-8638, 2019

PMID: 31705882

BioModels-15 years of sharing computational models in life science.
Malik-Sheriff RS, Glont M, Nguyen TVN, Tiwari K, Roberts MG, Xavier A, Vu MT, Men J, Maire M, Kananathan S, Fairbanks EL, Meyer JP, Arankalle C, Varusai TM, Knight-Schrijver V, Li L, Dueñas-Roca C, Dass G, Keating SM, Park YM, Buso N, Rodriguez N, Hucka M, Hermjakob H

Computational modelling has become increasingly common in life science research. To provide a platform to support universal sharing, easy accessibility and model reproducibility, BioModels (https://www.ebi.ac.uk/biomodels/), a repository for mathematical models, was established in 2005. The current BioModels platform allows submission of models encoded in diverse modelling formats, including SBML, CellML, PharmML, COMBINE archive, MATLAB, Mathematica, R, Python or C++. The models submitted to BioModels are curated to verify the computational representation of the biological process and the reproducibility of the simulation results in the reference publication. The curation also involves encoding models in standard formats and annotation with controlled vocabularies following MIRIAM (minimal information required in the annotation of biochemical models) guidelines. BioModels now accepts large-scale submission of auto-generated computational models. With gradual growth in content over 15 years, BioModels currently hosts about 2000 models from the published literature. With about 800 curated models, BioModels has become the world's largest repository of curated models and emerged as the third most used data resource after PubMed and Google Scholar among the scientists who use modelling in their research. Thus, BioModels benefits modellers by providing access to reliable and semantically enriched curated models in standard formats that are easy to share, reproduce and reuse.

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Nucleic acids research, 1, 1362-4962, 2019

PMID: 31701150

Open Access

Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion.
Johnston JM, Angyal A, Bauer RC, Hamby S, Suvarna SK, Baidžajevas K, Hegedus Z, Dear TN, Turner M, , Wilson HL, Goodall AH, Rader DJ, Shoulders CC, Francis SE, Kiss-Toth E

Macrophages drive atherosclerotic plaque progression and rupture; hence, attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced expression mediates the strong genetic association between the locus and increased CHD risk in man. However, we report here that myeloid-specific (m) deficiency reduces early atheroma formation and that m transgene expression increases atherogenesis. Mechanistically, m increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low-density lipoprotein uptake and the formation of lipid-laden foam cells. As and RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

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Science advances, 5, 2375-2548, 2019

PMID: 31692955

Open Access

Endogenous retroviral insertions drive non-canonical imprinting in extra-embryonic tissues.
Hanna CW, Pérez-Palacios R, Gahurova L, Schubert M, Krueger F, Biggins L, Andrews S, Colomé-Tatché M, Bourc'his D, Dean W, Kelsey G

Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on the parent of origin and is typically regulated by differential DNA methylation inherited from gametes. Imprinting is pervasive in murine extra-embryonic lineages, and uniquely, the imprinting of several genes has been found to be conferred non-canonically through maternally inherited repressive histone modification H3K27me3. However, the underlying regulatory mechanisms of non-canonical imprinting in post-implantation development remain unexplored.

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Genome biology, 20, 1474-760X, 2019

PMID: 31665063

Open Access