Life Sciences Research for Lifelong Health

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

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, 225, 2019

PMID: 31665063

Open Access

Tet3 regulates cellular identity and DNA methylation in neural progenitor cells.
Santiago M, Antunes C, Guedes M, Iacovino M, Kyba M, Reik W, Sousa N, Pinto L, Branco MR, Marques CJ

TET enzymes oxidize 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), a process thought to be intermediary in an active DNA demethylation mechanism. Notably, 5hmC is highly abundant in the brain and in neuronal cells. Here, we interrogated the function of Tet3 in neural precursor cells (NPCs), using a stable and inducible knockdown system and an in vitro neural differentiation protocol. We show that Tet3 is upregulated during neural differentiation, whereas Tet1 is downregulated. Surprisingly, Tet3 knockdown led to a de-repression of pluripotency-associated genes such as Oct4, Nanog or Tcl1, with concomitant hypomethylation. Moreover, in Tet3 knockdown NPCs, we observed the appearance of OCT4-positive cells forming cellular aggregates, suggesting de-differentiation of the cells. Notably, Tet3 KD led to a genome-scale loss of DNA methylation and hypermethylation of a smaller number of CpGs that are located at neurogenesis-related genes and at imprinting control regions (ICRs) of Peg10, Zrsr1 and Mcts2 imprinted genes. Overall, our results suggest that TET3 is necessary to maintain silencing of pluripotency genes and consequently neural stem cell identity, possibly through regulation of DNA methylation levels in neural precursor cells.

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Cellular and molecular life sciences : CMLS, , 1420-9071, , 2019

PMID: 31646359

Voices in methods development.
Anikeeva P, Boyden E, Brangwynne C, Cissé II, Fiehn O, Fromme P, Gingras AC, Greene CS, Heard E, Hell SW, Hillman E, Jensen GJ, Karchin R, Kiessling LL, Kleinstiver BP, Knight R, Kukura P, Lancaster MA, Loman N, Looger L, Lundberg E, Luo Q, Miyawaki A, Myers EW, Nolan GP, Picotti P, Reik W, Sauer M, Shalek AK, Shendure J, Slavov N, Tanay A, Troyanskaya O, van Valen D, Wang HW, Yi C, Yin P, Zernicka-Goetz M, Zhuang X

Nature methods, 16, 1548-7105, 945-951, 2019

PMID: 31562479

Transcription factors make the right contacts.
Rugg-Gunn PJ

Nature cell biology, , 1476-4679, , 2019

PMID: 31548607

Mechanisms of early placental development in mouse and humans.
Hemberger M, Hanna CW, Dean W

The importance of the placenta in supporting mammalian development has long been recognized, but our knowledge of the molecular, genetic and epigenetic requirements that underpin normal placentation has remained remarkably under-appreciated. Both the in vivo mouse model and in vitro-derived murine trophoblast stem cells have been invaluable research tools for gaining insights into these aspects of placental development and function, with recent studies starting to reshape our view of how a unique epigenetic environment contributes to trophoblast differentiation and placenta formation. These advances, together with recent successes in deriving human trophoblast stem cells, open up new and exciting prospects in basic and clinical settings that will help deepen our understanding of placental development and associated disorders of pregnancy.

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Nature reviews. Genetics, , 1471-0064, , 2019

PMID: 31534202

Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.
Stuart HT, Stirparo GG, Lohoff T, Bates LE, Kinoshita M, Lim CY, Sousa EJ, Maskalenka K, Radzisheuskaya A, Malcolm AA, Alves MRP, Lloyd RL, Nestorowa S, Humphreys P, Mansfield W, Reik W, Bertone P, Nichols J, Göttgens B, Silva JCR

Understanding how cell identity transitions occur and whether there are multiple paths between the same beginning and end states are questions of wide interest. Here we show that acquisition of naive pluripotency can follow transcriptionally and mechanistically distinct routes. Starting from post-implantation epiblast stem cells (EpiSCs), one route advances through a mesodermal state prior to naive pluripotency induction, whereas another transiently resembles the early inner cell mass and correspondingly gains greater developmental potency. These routes utilize distinct signaling networks and transcription factors but subsequently converge on the same naive endpoint, showing surprising flexibility in mechanisms underlying identity transitions and suggesting that naive pluripotency is a multidimensional attractor state. These route differences are reconciled by precise expression of Oct4 as a unifying, essential, and sufficient feature. We propose that fine-tuned regulation of this "transition factor" underpins multidimensional access to naive pluripotency, offering a conceptual framework for understanding cell identity transitions.

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Cell stem cell, , 1875-9777, , 2019

PMID: 31422912

Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1.
Martin-Herranz DE, Aref-Eshghi E, Bonder MJ, Stubbs TM, Choufani S, Weksberg R, Stegle O, Sadikovic B, Reik W, Thornton JM

Epigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery.

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Genome biology, 20, 1474-760X, 146, 2019

PMID: 31409373

Open Access

DNA methylation and mRNA expression of imprinted genes in blastocysts derived from an improved in vitro maturation method for oocytes from small antral follicles in polycystic ovary syndrome patients.
Saenz-de-Juano MD, Ivanova E, Romero S, Lolicato F, Sánchez F, Van Ranst H, Krueger F, Segonds-Pichon A, De Vos M, Andrews S, Smitz J, Kelsey G, Anckaert E

Does imprinted DNA methylation or imprinted gene expression differ between human blastocysts from conventional ovarian stimulation (COS) and an optimized two-step IVM method (CAPA-IVM) in age-matched polycystic ovary syndrome (PCOS) patients?

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Human reproduction (Oxford, England), 34, 1460-2350, 1640-1649, 2019

PMID: 31398248

Neuronal XBP-1 Activates Intestinal Lysosomes to Improve Proteostasis in C. elegans.
Imanikia S, Özbey NP, Krueger C, Casanueva MO, Taylor RC

The unfolded protein response of the endoplasmic reticulum (UPR) is a crucial mediator of secretory pathway homeostasis. Expression of the spliced and active form of the UPR transcription factor XBP-1, XBP-1s, in the nervous system triggers activation of the UPR in the intestine of Caenorhabditis elegans (C. elegans) through release of a secreted signal, leading to increased longevity. We find that expression of XBP-1s in the neurons or intestine of the worm strikingly improves proteostasis in multiple tissues, through increased clearance of toxic proteins. To identify the mechanisms behind this enhanced proteostasis, we conducted intestine-specific RNA-seq analysis to identify genes upregulated in the intestine when XBP-1s is expressed in neurons. This revealed that neuronal XBP-1s increases the expression of genes involved in lysosome function. Lysosomes in the intestine of animals expressing neuronal XBP-1s are more acidic, and lysosomal protease activity is higher. Moreover, intestinal lysosome function is necessary for enhanced lifespan and proteostasis. These findings suggest that activation of the UPR in the intestine through neuronal signaling can increase the activity of lysosomes, leading to extended longevity and improved proteostasis across tissues.

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Current biology : CB, 29, 1879-0445, 2322-2338.e7, 2019

PMID: 31303493

Open Access

Establishment of porcine and human expanded potential stem cells.
Gao X, Nowak-Imialek M, Chen X, Chen D, Herrmann D, Ruan D, Chen ACH, Eckersley-Maslin MA, Ahmad S, Lee YL, Kobayashi T, Ryan D, Zhong J, Zhu J, Wu J, Lan G, Petkov S, Yang J, Antunes L, Campos LS, Fu B, Wang S, Yong Y, Wang X, Xue SG, Ge L, Liu Z, Huang Y, Nie T, Li P, Wu D, Pei D, Zhang Y, Lu L, Yang F, Kimber SJ, Reik W, Zou X, Shang Z, Lai L, Surani A, Tam PPL, Ahmed A, Yeung WSB, Teichmann SA, Niemann H, Liu P

We recently derived mouse expanded potential stem cells (EPSCs) from individual blastomeres by inhibiting the critical molecular pathways that predispose their differentiation. EPSCs had enriched molecular signatures of blastomeres and possessed developmental potency for all embryonic and extra-embryonic cell lineages. Here, we report the derivation of porcine EPSCs, which express key pluripotency genes, are genetically stable, permit genome editing, differentiate to derivatives of the three germ layers in chimeras and produce primordial germ cell-like cells in vitro. Under similar conditions, human embryonic stem cells and induced pluripotent stem cells can be converted, or somatic cells directly reprogrammed, to EPSCs that display the molecular and functional attributes reminiscent of porcine EPSCs. Importantly, trophoblast stem-cell-like cells can be generated from both human and porcine EPSCs. Our pathway-inhibition paradigm thus opens an avenue for generating mammalian pluripotent stem cells, and EPSCs present a unique cellular platform for translational research in biotechnology and regenerative medicine.

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Nature cell biology, 21, 1476-4679, 687-699, 2019

PMID: 31160711

Long-range enhancer-promoter contacts in gene expression control.
Schoenfelder S, Fraser P

Spatiotemporal gene expression programmes are orchestrated by transcriptional enhancers, which are key regulatory DNA elements that engage in physical contacts with their target-gene promoters, often bridging considerable genomic distances. Recent progress in genomics, genome editing and microscopy methodologies have enabled the genome-wide mapping of enhancer-promoter contacts and their functional dissection. In this Review, we discuss novel concepts on how enhancer-promoter interactions are established and maintained, how the 3D architecture of mammalian genomes both facilitates and constrains enhancer-promoter contacts, and the role they play in gene expression control during normal development and disease.

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Nature reviews. Genetics, , 1471-0064, , 2019

PMID: 31086298

A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice.
Sendžikaitė G, Hanna CW, Stewart-Morgan KR, Ivanova E, Kelsey G

DNA methyltransferases (DNMTs) deposit DNA methylation, which regulates gene expression and is essential for mammalian development. Histone post-translational modifications modulate the recruitment and activity of DNMTs. The PWWP domains of DNMT3A and DNMT3B are posited to interact with histone 3 lysine 36 trimethylation (H3K36me3); however, the functionality of this interaction for DNMT3A remains untested in vivo. Here we present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain. The mutation causes dominant postnatal growth retardation. At the molecular level, it results in progressive DNA hypermethylation across domains marked by H3K27me3 and bivalent chromatin, and de-repression of developmental regulatory genes in adult hypothalamus. Evaluation of non-CpG methylation, a marker of de novo methylation, further demonstrates the altered recruitment and activity of DNMT3A at bivalent domains. This work provides key molecular insights into the function of the DNMT3A-PWWP domain and role of DNMT3A in regulating postnatal growth.

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Nature communications, 10, 2041-1723, 1884, 2019

PMID: 31015495

Open Access

TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn.
Montalbán-Loro R, Lozano-Ureña A, Ito M, Krueger C, Reik W, Ferguson-Smith AC, Ferrón SR

Ten-eleven-translocation (TET) proteins catalyze DNA hydroxylation, playing an important role in demethylation of DNA in mammals. Remarkably, although hydroxymethylation levels are high in the mouse brain, the potential role of TET proteins in adult neurogenesis is unknown. We show here that a non-catalytic action of TET3 is essentially required for the maintenance of the neural stem cell (NSC) pool in the adult subventricular zone (SVZ) niche by preventing premature differentiation of NSCs into non-neurogenic astrocytes. This occurs through direct binding of TET3 to the paternal transcribed allele of the imprinted gene Small nuclear ribonucleoprotein-associated polypeptide N (Snrpn), contributing to transcriptional repression of the gene. The study also identifies BMP2 as an effector of the astrocytic terminal differentiation mediated by SNRPN. Our work describes a novel mechanism of control of an imprinted gene in the regulation of adult neurogenesis through an unconventional role of TET3.

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Nature communications, 10, 2041-1723, 1726, 2019

PMID: 30979904

Open Access

Correction to: Comparison of whole-genome bisulfite sequencing library preparation strategies identifies sources of biases affecting DNA methylation data.
Olova N, Krueger F, Andrews S, Oxley D, Berrens RV, Branco MR, Reik W

Following publication of the original article [1], it was reported that the incorrect "Additional file 3" was published. The correct additional file is given below.

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Genome biology, 20, 1474-760X, 43, 2019

PMID: 30795792

Open Access

Genomic Imprinting and Physiological Processes in Mammals.
Tucci V, Isles AR, Kelsey G, Ferguson-Smith AC,

Complex multicellular organisms, such as mammals, express two complete sets of chromosomes per nucleus, combining the genetic material of both parents. However, epigenetic studies have demonstrated violations to this rule that are necessary for mammalian physiology; the most notable parental allele expression phenomenon is genomic imprinting. With the identification of endogenous imprinted genes, genomic imprinting became well-established as an epigenetic mechanism in which the expression pattern of a parental allele influences phenotypic expression. The expanding study of genomic imprinting is revealing a significant impact on brain functions and associated diseases. Here, we review key milestones in the field of imprinting and discuss mechanisms and systems in which imprinted genes exert a significant role.

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Cell, 176, 1097-4172, 952-965, 2019

PMID: 30794780

Multi-Omics and Genome-Scale Modeling Reveal a Metabolic Shift During C. Elegans Ageing.
Hastings J, Mains A, Virk B, Rodriguez N, Murdoch S, Pearce J, Bergmann S, Le Novère N, Casanueva O

In this contribution, we describe a multi-omics systems biology study of the metabolic changes that occur during aging in . Sampling several time points from young adulthood until early old age, our study covers the full duration of aging and include transcriptomics, and targeted MS-based metabolomics. In order to focus on the metabolic changes due to age we used two strains that are metabolically close to wild-type, yet are conditionally non-reproductive. Using these data in combination with a whole-genome model of the metabolism of and mathematical modeling, we predicted metabolic fluxes during early aging. We find that standard Flux Balance Analysis does not accurately predict measured fluxes nor age-related changes associated with the Citric Acid cycle. We present a novel Flux Balance Analysis method where we combined biomass production and targeted metabolomics information to generate an objective function that is more suitable for aging studies. We validated this approach with a detailed case study of the age-associated changes in the Citric Acid cycle. Our approach provides a comprehensive time-resolved multi-omics and modeling resource for studying the metabolic changes during normal aging in .

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Frontiers in molecular biosciences, 6, 2296-889X, 2, 2019

PMID: 30788345

Open Access

A single-cell molecular map of mouse gastrulation and early organogenesis.
Pijuan-Sala B, Griffiths JA, Guibentif C, Hiscock TW, Jawaid W, Calero-Nieto FJ, Mulas C, Ibarra-Soria X, Tyser RCV, Ho DLL, Reik W, Srinivas S, Simons BD, Nichols J, Marioni JC, Göttgens B

Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time points ranging from 6.5 to 8.5 days post-fertilization. We construct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we use single-cell profiling to show that Tal1 chimeric embryos display defects in early mesoderm diversification, and we thus demonstrate how combining temporal and transcriptional information can illuminate gene function. Together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of in vitro differentiation protocols for regenerative medicine.

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Nature, , 1476-4687, , 2019

PMID: 30787436

Open Access

Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity.
Linker SM, Urban L, Clark SJ, Chhatriwala M, Amatya S, McCarthy DJ, Ebersberger I, Vallier L, Reik W, Stegle O, Bonder MJ

Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic features, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue or cell type and its determinants remains poorly understood.

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Genome biology, 20, 1474-760X, 30, 2019

PMID: 30744673

Open Access

Dppa2 and Dppa4 directly regulate the Dux-driven zygotic transcriptional program.
Eckersley-Maslin M, Alda-Catalinas C, Blotenburg M, Kreibich E, Krueger C, Reik W

The molecular regulation of zygotic genome activation (ZGA) in mammals remains an exciting area of research. Primed mouse embryonic stem cells contain a rare subset of "2C-like" cells that are epigenetically and transcriptionally similar to the two-cell embryo and thus represent an in vitro approximation for studying ZGA transcription regulation. Recently, the transcription factor Dux, expressed in the minor wave of ZGA, was described to activate many downstream ZGA transcripts. However, it remains unknown what upstream maternal factors initiate ZGA in either a Dux-dependent or Dux-independent manner. Here we performed a candidate-based overexpression screen, identifying, among others, developmental pluripotency-associated 2 (Dppa2) and Dppa4 as positive regulators of 2C-like cells and transcription of ZGA genes. In the germline, promoter DNA demethylation coincides with expression of Dppa2 and Dppa4, which remain expressed until embryonic day 7.5 (E7.5), when their promoters are remethylated. Furthermore, Dppa2 and Dppa4 are also expressed during induced pluripotent stem cell (iPSC) reprogramming at the time that 2C-like transcription transiently peaks. Through a combination of overexpression, knockdown, knockout, and rescue experiments together with transcriptional analyses, we show that Dppa2 and Dppa4 directly regulate the 2C-like cell population and associated transcripts, including Dux and the Zscan4 cluster. Importantly, we teased apart the molecular hierarchy in which the 2C-like transcriptional program is initiated and stabilized. Dppa2 and Dppa4 require Dux to initiate 2C-like transcription, suggesting that they act upstream by directly regulating Dux. Supporting this, ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analysis revealed that Dppa2 and Dppa4 bind to the Dux promoter and gene body and drive its expression. Zscan4c is also able to induce 2C-like cells in wild-type cells but, in contrast to Dux, can no longer do so in Dppa2/4 double-knockout cells, suggesting that it may act to stabilize rather than drive the transcriptional network. Our findings suggest a model in which Dppa2/4 binding to the Dux promoter leads to Dux up-regulation and activation of the 2C-like transcriptional program, which is subsequently reinforced by Zscan4c.

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Genes & development, 33, 1549-5477, 194-208, 2019

PMID: 30692203

Open Access

Transcriptional Heterogeneity in Naive and Primed Human Pluripotent Stem Cells at Single-Cell Resolution.
Messmer T, von Meyenn F, Savino A, Santos F, Mohammed H, Lun ATL, Marioni JC, Reik W

Conventional human embryonic stem cells are considered to be primed pluripotent but can be induced to enter a naive state. However, the transcriptional features associated with naive and primed pluripotency are still not fully understood. Here we used single-cell RNA sequencing to characterize the differences between these conditions. We observed that both naive and primed populations were mostly homogeneous with no clear lineage-related structure and identified an intermediate subpopulation of naive cells with primed-like expression. We found that the naive-primed pluripotency axis is preserved across species, although the timing of the transition to a primed state is species specific. We also identified markers for distinguishing human naive and primed pluripotency as well as strong co-regulatory relationships between lineage markers and epigenetic regulators that were exclusive to naive cells. Our data provide valuable insights into the transcriptional landscape of human pluripotency at a cellular and genome-wide resolution.

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Cell reports, 26, 2211-1247, 815-824.e4, 2019

PMID: 30673604

Open Access

Bio-On-Magnetic-Beads (BOMB): Open platform for high-throughput nucleic acid extraction and manipulation.
Oberacker P, Stepper P, Bond DM, Höhn S, Focken J, Meyer V, Schelle L, Sugrue VJ, Jeunen GJ, Moser T, Hore SR, von Meyenn F, Hipp K, Hore TA, Jurkowski TP

Current molecular biology laboratories rely heavily on the purification and manipulation of nucleic acids. Yet, commonly used centrifuge- and column-based protocols require specialised equipment, often use toxic reagents, and are not economically scalable or practical to use in a high-throughput manner. Although it has been known for some time that magnetic beads can provide an elegant answer to these issues, the development of open-source protocols based on beads has been limited. In this article, we provide step-by-step instructions for an easy synthesis of functionalised magnetic beads, and detailed protocols for their use in the high-throughput purification of plasmids, genomic DNA, RNA and total nucleic acid (TNA) from a range of bacterial, animal, plant, environmental and synthetic sources. We also provide a bead-based protocol for bisulfite conversion and size selection of DNA and RNA fragments. Comparison to other methods highlights the capability, versatility, and extreme cost-effectiveness of using magnetic beads. These open-source protocols and the associated webpage (https://bomb.bio) can serve as a platform for further protocol customisation and community engagement.

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PLoS biology, 17, 1545-7885, e3000107, 2019

PMID: 30629605

Open Access

The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome.
Gdula MR, Nesterova TB, Pintacuda G, Godwin J, Zhan Y, Ozadam H, McClellan M, Moralli D, Krueger F, Green CM, Reik W, Kriaucionis S, Heard E, Dekker J, Brockdorff N

The inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), A/B compartments and formation of two mega-domains. Here we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 mutant cells reveals the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including A/B compartments and partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred following SmcHD1 knockout in a somatic cell model, but in this case, independent of Xi gene derepression. We conclude that SmcHD1 is a key factor in defining the unique chromosome architecture of Xi.

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Nature communications, 10, 2041-1723, 30, 2019

PMID: 30604745

Open Access

Modeling Meets Metabolomics-The WormJam Consensus Model as Basis for Metabolic Studies in the Model Organism .
Witting M, Hastings J, Rodriguez N, Joshi CJ, Hattwell JPN, Ebert PR, van Weeghel M, Gao AW, Wakelam MJO, Houtkooper RH, Mains A, Le Novère N, Sadykoff S, Schroeder F, Lewis NE, Schirra HJ, Kaleta C, Casanueva O

Metabolism is one of the attributes of life and supplies energy and building blocks to organisms. Therefore, understanding metabolism is crucial for the understanding of complex biological phenomena. Despite having been in the focus of research for centuries, our picture of metabolism is still incomplete. Metabolomics, the systematic analysis of all small molecules in a biological system, aims to close this gap. In order to facilitate such investigations a blueprint of the metabolic network is required. Recently, several metabolic network reconstructions for the model organism have been published, each having unique features. We have established the WormJam Community to merge and reconcile these (and other unpublished models) into a single consensus metabolic reconstruction. In a series of workshops and annotation seminars this model was refined with manual correction of incorrect assignments, metabolite structure and identifier curation as well as addition of new pathways. The WormJam consensus metabolic reconstruction represents a rich data source not only for network-based approaches like flux balance analysis, but also for metabolomics, as it includes a database of metabolites present in , which can be used for annotation. Here we present the process of model merging, correction and curation and give a detailed overview of the model. In the future it is intended to expand the model toward different tissues and put special emphasizes on lipid metabolism and secondary metabolism including ascaroside metabolism in accordance to their central role in physiology.

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Frontiers in molecular biosciences, 5, 2296-889X, 96, 2018

PMID: 30488036

Trophoblast organoids as a model for maternal-fetal interactions during human placentation.
Turco MY, Gardner L, Kay RG, Hamilton RS, Prater M, Hollinshead MS, McWhinnie A, Esposito L, Fernando R, Skelton H, Reimann F, Gribble FM, Sharkey A, Marsh SGE, O'Rahilly S, Hemberger M, Burton GJ, Moffett A

The placenta is the extraembryonic organ that supports the fetus during intrauterine life. Although placental dysfunction results in major disorders of pregnancy with immediate and lifelong consequences for the mother and child, our knowledge of the human placenta is limited owing to a lack of functional experimental models. After implantation, the trophectoderm of the blastocyst rapidly proliferates and generates the trophoblast, the unique cell type of the placenta. In vivo, proliferative villous cytotrophoblast cells differentiate into two main sub-populations: syncytiotrophoblast, the multinucleated epithelium of the villi responsible for nutrient exchange and hormone production, and extravillous trophoblast cells, which anchor the placenta to the maternal decidua and transform the maternal spiral arteries. Here we describe the generation of long-term, genetically stable organoid cultures of trophoblast that can differentiate into both syncytiotrophoblast and extravillous trophoblast. We used human leukocyte antigen (HLA) typing to confirm that the organoids were derived from the fetus, and verified their identities against four trophoblast-specific criteria. The cultures organize into villous-like structures, and we detected the secretion of placental-specific peptides and hormones, including human chorionic gonadotropin (hCG), growth differentiation factor 15 (GDF15) and pregnancy-specific glycoprotein (PSG) by mass spectrometry. The organoids also differentiate into HLA-G extravillous trophoblast cells, which vigorously invade in three-dimensional cultures. Analysis of the methylome reveals that the organoids closely resemble normal first trimester placentas. This organoid model will be transformative for studying human placental development and for investigating trophoblast interactions with the local and systemic maternal environment.

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Nature, , 1476-4687, , 2018

PMID: 30487605

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity.
Hahn O, Stubbs TM, Reik W, Grönke S, Beyer A, Partridge L

Dietary, pharmacological and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, whole-genome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.

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PLoS genetics, 14, 1553-7404, e1007766, 2018

PMID: 30462643

Open Access