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鶹Ƶ Publications database contains details of all publications resulting from our research groups and  Pre-prints by 鶹Ƶ authors can be viewed on the 鶹Ƶ's . We believe that free and open access to the outputs of publicly‐funded research offers significant social and economic benefits, as well as aiding the development of new research. We are working to provide Open Access to as many publications as possible and these can be identified below by the padlock icon. Where this hasn't been possible, subscriptions may be required to view the full text.
 

Hua Y, Vella G, Rambow F, Allen E, Martinez AA, Duhamel M, Takeda A, Jalkanen S, Junius S, Smeets A, Nittner D, Dimmeler S, Hehlgans T, Liston A, Bosisio FM, Floris G, Laoui D, Hollmén M, Lambrechts D, Merchiers P, Marine JC, Schlenner S, Bergers G Immunology

n/a

+view abstract Cancer cell, PMID: 36626867

Open Access
Maskalenka K, Alagöz G, Krueger F, Wright J, Rostovskaya M, Nakhuda A, Bendall A, Krueger C, Walker S, Scally A, Rugg-Gunn PJ Epigenetics,Gene Targeting, Bioinformatics, Imaging

Gene duplication events can drive evolution by providing genetic material for new gene functions, and create opportunities for diverse developmental strategies to emerge between species. To study the contribution of duplicated genes to human early development, we examined the evolution and function of NANOGP1, a tandem duplicate of the transcription factor NANOG. We found that NANOGP1 and NANOG have overlapping but distinct expression profiles, with high NANOGP1 expression restricted to early epiblast cells and naïve-state pluripotent stem cells. Sequence analysis and epitope-tagging revealed that NANOGP1 is protein-coding with an intact homeobox domain. The duplication that created NANOGP1 occurred earlier in primate evolution than previously thought and has been retained only in great apes, whereas Old World monkeys have disabled the gene in different ways including homeodomain point mutations. NANOGP1 is a strong inducer of naïve pluripotency; however, unlike NANOG, it is not required to maintain the undifferentiated status of human naïve pluripotent cells. By retaining expression, sequence and partial functional conservation with its ancestral copy, NANOGP1 exemplifies how gene duplication and subfunctionalisation can contribute to transcription factor activity in human pluripotency and development.

+view abstract Development (Cambridge, England), PMID: 36621005

Liston A, Yshii L Immunology

n/a

+view abstract Nature immunology, PMID: 36596892

Bonaud A, Gargowitsch L, Gilbert SM, Rajan E, Canales-Herrerias P, Stockholm D, Rahman NF, Collins MO, Taskiran H, Hill DL, Alloatti A, Alouche N, Balor S, Soldan V, Gillet D, Barbier J, Bachelerie F, Smith KGC, Jellusova J, Bruhns P, Amigorena S, Balabanian K, Linterman MA, Peden AA, Espéli M Immunology

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Sec22b as a unique and critical regulator of plasma cell maintenance and function. In the absence of Sec22b, plasma cells were hardly detectable and serum antibody titers were dramatically reduced. Accordingly, -deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b contributes to efficient antibody secretion and is a central regulator of plasma cell maintenance through the regulation of their transcriptional identity and of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil an essential and nonredundant role for Sec22b as a regulator of plasma cell fitness and of the humoral immune response.

+view abstract Proceedings of the National Academy of Sciences of the United States of America, PMID: 36595686

Open Access
Lopes JS, Ivanova E, Ruiz S, Andrews S, Kelsey G, Coy P Epigenetics,Bioinformatics

Controlled ovarian stimulation is a necessary step in some assisted reproductive procedures allowing a higher collection of female gametes. However, consequences of this stimulation for the gamete or the offspring have been shown in several mammals. Most studies used comparisons between oocytes from different donors, which may contribute to different responses. In this work, we use the bovine model in which each animal serves as its own control. DNA methylation profiles were obtained by single-cell whole-genome bisulfite sequencing of oocytes from pre-ovulatory unstimulated follicles compared to oocytes from stimulated follicles. Results show that the global percentage of methylation was similar between groups, but the percentage of methylation was lower for non-stimulated oocytes in the imprinted genes , , and and higher in when compared to stimulated oocytes. Differences were also found in CGI of imprinted genes: higher methylation was found among non-stimulated oocytes in (), , , , and . In another region around , the methylation percentage was lower for non-stimulated oocytes when compared to stimulated oocytes. Data drawn from this study might help to understand the molecular reasons for the appearance of certain syndromes in assisted reproductive technologies-derived offspring.

+view abstract International journal of molecular sciences, PMID: 36555801

Open Access
Samant RS, Batista S, Larance M, Ozer B, Milton CI, Bludau I, Wu E, Biggins L, Andrews S, Hervieu A, Johnston HE, Al-Lazikhani B, Lamond AI, Clarke PA, Workman P Signalling,Bioinformatics

The molecular chaperone heat shock protein 90 (HSP90) works in concert with co-chaperones to stabilize its client proteins, which include multiple drivers of oncogenesis and malignant progression. Pharmacologic inhibitors of HSP90 have been observed to exert a wide range of effects on the proteome, including depletion of client proteins, induction of heat shock proteins, dissociation of co-chaperones from HSP90, disruption of client protein signaling networks, and recruitment of the protein ubiquitylation and degradation machinery-suggesting widespread remodeling of cellular protein complexes. However, proteomics studies to date have focused on inhibitor-induced changes in total protein levels, often overlooking protein complex alterations. Here, we use size-exclusion chromatography in combination with mass spectrometry (SEC-MS) to characterize the early changes in native protein complexes following treatment with the HSP90 inhibitor tanespimycin (17-AAG) for 8 h in the HT29 colon adenocarcinoma cell line. After confirming the signature cellular response to HSP90 inhibition (e.g., induction of heat shock proteins, decreased total levels of client proteins), we were surprised to find only modest perturbations to the global distribution of protein elution profiles in inhibitor-treated HT29 cells at this relatively early time-point. Similarly, co-chaperones that co-eluted with HSP90 displayed no clear difference between control and treated conditions. However, two distinct analysis strategies identified multiple inhibitor-induced changes, including known and unknown components of the HSP90-dependent proteome. We validate two of these-the actin-binding protein Anillin and the mitochondrial isocitrate dehydrogenase 3 complex-as novel HSP90 inhibitor-modulated proteins. We present this dataset as a resource for the HSP90, proteostasis, and cancer communities (https://www.bioinformatics.babraham.ac.uk/shiny/HSP90/SEC-MS/), laying the groundwork for future mechanistic and therapeutic studies related to HSP90 pharmacology. Data are available via ProteomeXchange with identifier PXD033459.

+view abstract Molecular & cellular proteomics : MCP, PMID: 36549590

Ni Z, Wölk M, Jukes G, Mendivelso Espinosa K, Ahrends R, Aimo L, Alvarez-Jarreta J, Andrews S, Andrews R, Bridge A, Clair GC, Conroy MJ, Fahy E, Gaud C, Goracci L, Hartler J, Hoffmann N, Kopczyinki D, Korf A, Lopez-Clavijo AF, Malik A, Ackerman JM, Molenaar MR, O'Donovan C, Pluskal T, Shevchenko A, Slenter D, Siuzdak G, Kutmon M, Tsugawa H, Willighagen EL, Xia J, O'Donnell VB, Fedorova M Signalling,Bioinformatics, Lipidomics

Progress in mass spectrometry lipidomics has led to a rapid proliferation of studies across biology and biomedicine. These generate extremely large raw datasets requiring sophisticated solutions to support automated data processing. To address this, numerous software tools have been developed and tailored for specific tasks. However, for researchers, deciding which approach best suits their application relies on ad hoc testing, which is inefficient and time consuming. Here we first review the data processing pipeline, summarizing the scope of available tools. Next, to support researchers, LIPID MAPS provides an interactive online portal listing open-access tools with a graphical user interface. This guides users towards appropriate solutions within major areas in data processing, including (1) lipid-oriented databases, (2) mass spectrometry data repositories, (3) analysis of targeted lipidomics datasets, (4) lipid identification and (5) quantification from untargeted lipidomics datasets, (6) statistical analysis and visualization, and (7) data integration solutions. Detailed descriptions of functions and requirements are provided to guide customized data analysis workflows.

+view abstract Nature methods, PMID: 36543939

Osma-Garcia IC, Capitan-Sobrino D, Mouysset M, Aubert Y, Maloudi O, Turner M, Diaz-Muñoz MD Immunology

B cell lymphopoiesis requires dynamic modulation of the B cell transcriptome for timely coordination of somatic mutagenesis and DNA repair in progenitor B (pro-B) cells. Here, we show that, in pro-B cells, the RNA-binding proteins T cell intracellular antigen 1 (TIA1) and TIA1-like protein (TIAL1) act redundantly to enable developmental progression. They are global splicing regulators that control the expression of hundreds of mRNAs, including those involved in DNA damage repair. Mechanistically, TIA1 and TIAL1 bind to 5' splice sites for exon definition, splicing, and expression of DNA damage sensors, such as Chek2 and Rif1. In their absence, pro-B cells show exacerbated DNA damage, altered P53 expression, and increased cell death. Our study uncovers the importance of tight regulation of RNA splicing by TIA1 and TIAL1 for the expression of integrative transcriptional programs that control DNA damage sensing and repair during B cell development.

+view abstract Cell reports, PMID: 36543128

Gardner JM, Liston A Immunology

Recent studies shed light on new populations and potential roles of Aire and RORγt antigen-presenting cells-including unique subsets with surprising properties-in immune homeostasis and host-microbe interactions.

+view abstract Science immunology, PMID: 36525506

Rayon T, van den Ameele J Signalling, Epigenetics

In preprint

+view abstract Development (Cambridge, England), PMID: 36515644

von Meyenn F, Berrens RV, Andrews S, Santos F, Collier AJ, Krueger F, Osorno R, Dean W, Rugg-Gunn PJ, Reik W Epigenetics,Bioinformatics

n/a

+view abstract Developmental cell, PMID: 36473463

Cesare E, Urciuolo A, Stuart HT, Torchio E, Gesualdo A, Laterza C, Gagliano O, Martewicz S, Cui M, Manfredi A, Di Filippo L, Sabatelli P, Squarzoni S, Zorzan I, Betto RM, Martello G, Cacchiarelli D, Luni C, Elvassore N Epigenetics

The establishment of in vitro naive human pluripotent stem cell cultures opened new perspectives for the study of early events in human development. The role of several transcription factors and signaling pathways have been characterized during maintenance of human naive pluripotency. However, little is known about the role exerted by the extracellular matrix (ECM) and its three-dimensional (3D) organization. Here, using an unbiased and integrated approach combining microfluidic cultures with transcriptional, proteomic, and secretome analyses, we found that naive, but not primed, hiPSC colonies are characterized by a self-organized ECM-rich microenvironment. Based on this, we developed a 3D culture system that supports robust long-term feeder-free self-renewal of naive hiPSCs and also allows direct and timely developmental morphogenesis simply by modulating the signaling environment. Our study opens new perspectives for future applications of naive hiPSCs to study critical stages of human development in 3D starting from a single cell.

+view abstract Cell stem cell, PMID: 36459970

Foster WS, Lee JL, Thakur N, Newman J, Spencer AJ, Davies S, Woods D, Godfrey L, Hay IM, Innocentin S, Yam-Puc JC, Horner EC, Sharpe HJ, Thaventhiran JE, Bailey D, Lambe T, Linterman MA Immunology

Emergence from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been facilitated by the rollout of effective vaccines. Successful vaccines generate high-affinity plasma blasts and long-lived protective memory B cells. Here, we show a requirement for T follicular helper (Tfh) cells and the germinal center reaction for optimal serum antibody and memory B cell formation after ChAdOx1 nCoV-19 vaccination. We found that Tfh cells play an important role in expanding antigen-specific B cells while identifying Tfh-cell-dependent and -independent memory B cell subsets. Upon secondary vaccination, germinal center B cells generated during primary immunizations can be recalled as germinal center B cells again. Likewise, primary immunization GC-Tfh cells can be recalled as either Tfh or Th1 cells, highlighting the pluripotent nature of Tfh cell memory. This study demonstrates that ChAdOx1 nCoV-19-induced germinal centers are a critical source of humoral immunity.

+view abstract Cell reports. Medicine, PMID: 36455555

Open Access
Terry LE, Arige V, Neumann J, Wahl AM, Knebel TR, Chaffer JW, Malik S, Liston A, Humblet-Baron S, Bultynck G, Yule DI Immunology

Mutations in all subtypes of the inositol 1,4,5-trisphosphate receptor Ca release channel are associated with human diseases. In this report, we investigated the functionality of three neuropathy-associated missense mutations in IPR3 (V615M, T1424M, and R2524C). The mutants only exhibited function when highly over-expressed compared to endogenous hIPR3. All variants resulted in elevated basal cytosolic Ca levels, decreased endoplasmic reticulum Ca store content, and constitutive store-operated Ca entry in the absence of any stimuli, consistent with a leaky IPR channel pore. These variants differed in channel function; when stably over-expressed the R2524C mutant was essentially dead, V615M was poorly functional, and T1424M exhibited activity greater than that of the corresponding wild-type following threshold stimulation. These results demonstrate that a common feature of these mutations is decreased IPR3 function. In addition, these mutations exhibit a novel phenotype manifested as a constitutively open channel, which inappropriately gates SOCE in the absence of stimulation.

+view abstract iScience, PMID: 36444295

Open Access
Hay IM, Shamin M, Caroe ER, Mohammed ASA, Svergun DI, Jeffries CM, Graham SC, Sharpe HJ, Deane JE Signalling

The type IIB receptor protein tyrosine phosphatases (R2B RPTPs) are cell surface transmembrane proteins that engage in cell adhesion via their extracellular domains (ECDs) and cell signaling via their cytoplasmic phosphatase domains. The ECDs of R2B RPTPs form stable, homophilic, trans interactions between adjacent cell membranes. Previous work has demonstrated how one family member, PTPRM, forms head-to-tail homodimers. However, as the interface was composed of residues conserved across the family, the determinants of homophilic specificity remain unknown. Here, we have solved the X-ray crystal structure of the membrane-distal, N-terminal domains of PTPRK that form a head-to-tail dimer consistent with intermembrane adhesion. Comparison with the PTPRM structure demonstrates inter-domain conformational differences that may define homophilic specificity. Using small-angle X-ray scattering, we determined the solution structures of the full-length ECDs of PTPRM and PTPRK, identifying that both are rigid, extended molecules that differ in their overall long-range conformation. Furthermore, we identify one residue, W351, within the interaction interface that differs between PTPRM and PTPRK and show that mutation to glycine, the equivalent residue in PTPRM, abolishes PTPRK dimer formation in vitro. This comparison of two members of the receptor tyrosine phosphatase family suggests that homophilic specificity is driven by a combination of shape complementarity and specific but limited sequence differences.

+view abstract The Journal of biological chemistry, PMID: 36436563

Hua Y, Vella G, Rambow F, Allen E, Antoranz Martinez A, Duhamel M, Takeda A, Jalkanen S, Junius S, Smeets A, Nittner D, Dimmeler S, Hehlgans T, Liston A, Bosisio FM, Floris G, Laoui D, Hollmén M, Lambrechts D, Merchiers P, Marine JC, Schlenner S, Bergers G Immunology

The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1 and PD1TCF1 CD8 T cell progenitors that differentiate into GrzBPD1 CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

+view abstract Cancer cell, PMID: 36423635

Willemsen M, Staels F, Gerbaux M, Neumann J, Schrijvers R, Meyts I, Humblet-Baron S, Liston A Immunology

Inborn errors of immunity are a heterogenous group of monogenic immunological disorders caused by mutations in genes with critical roles in the development, maintenance or function of the immune system. The genetic basis is frequently a mutation in a gene with restricted expression and/or function in immune cells, leading to an immune disorder. Several classes of inborn errors of immunity, however, result from mutation in genes that are ubiquitously expressed. Despite the genes participating in cellular processes conserved between cell types, immune cells are disproportionally affected, leading to inborn errors of immunity. Mutations in DNA replication, DNA repair or DNA damage response factors can result in monogenic human disease, some of which are classified as inborn error of immunity. Genetic defects in the DNA repair machinery are a well-known cause of TBNK severe combined immunodeficiency. An emerging class of inborn errors of immunity is those caused by mutations in DNA replication factors. Considerable heterogeneity exists within the DNA replication-associated inborn errors of immunity, with diverse immunological defects and clinical manifestations observed. These differences are suggestive for differential sensitivity of certain leukocyte subsets to deficiencies in specific DNA replication factors. Here, we provide an overview of DNA replication-associated inborn errors of immunity and discuss the emerging mechanistic insights that can explain the observed immunological heterogeneity.

+view abstract The Journal of allergy and clinical immunology, PMID: 36395985

Open Access
Matheson LS, Petkau G, Sáenz-Narciso B, D'Angeli V, McHugh J, Newman R, Munford H, West J, Chakraborty K, Roberts J, Łukasiak S, Díaz-Muñoz MD, Bell SE, Dimeloe S, Turner M Immunology

The ZFP36 family of RNA-binding proteins acts post-transcriptionally to repress translation and promote RNA decay. Studies of genes and pathways regulated by the ZFP36 family in CD4 T cells have focussed largely on cytokines, but their impact on metabolic reprogramming and differentiation is unclear. Using CD4 T cells lacking Zfp36 and Zfp36l1, we combined the quantification of mRNA transcription, stability, abundance and translation with crosslinking immunoprecipitation and metabolic profiling to determine how they regulate T cell metabolism and differentiation. Our results suggest that ZFP36 and ZFP36L1 act directly to limit the expression of genes driving anabolic processes by two distinct routes: by targeting transcription factors and by targeting transcripts encoding rate-limiting enzymes. These enzymes span numerous metabolic pathways including glycolysis, one-carbon metabolism and glutaminolysis. Direct binding and repression of transcripts encoding glutamine transporter SLC38A2 correlated with increased cellular glutamine content in ZFP36/ZFP36L1-deficient T cells. Increased conversion of glutamine to α-ketoglutarate in these cells was consistent with direct binding of ZFP36/ZFP36L1 to Gls (encoding glutaminase) and Glud1 (encoding glutamate dehydrogenase). We propose that ZFP36 and ZFP36L1 as well as glutamine and α-ketoglutarate are limiting factors for the acquisition of the cytotoxic CD4 T cell fate. Our data implicate ZFP36 and ZFP36L1 in limiting glutamine anaplerosis and differentiation of activated CD4 T cells, likely mediated by direct binding to transcripts of critical genes that drive these processes.

+view abstract Scientific reports, PMID: 36385275

Whyte CE, Tumes DJ, Liston A, Burton OT Immunology

Recent advances in flow cytometry have allowed high-dimensional characterization of biological phenomena, enabling breakthroughs in a multitude of fields. Despite the appreciation of the unique properties of antigens and fluorophores in high-parameter panel design, staining conditions are often standardized for short surface stains, regardless of antibody affinity or antigen accessibility. Here, we demonstrate how increasing antibody incubation times can lead to substantial improvements in sensitivity, maintaining specificity, and reducing background, while also significantly reducing the costs of high-parameter cytometry panels. Furthermore, overnight staining reduces the influence of interexperimental variability, assisting accurate pooling over experiments over extended time courses. We provide guidance on how to optimize staining conditions for diverse antigens, including how different fixation strategies can affect epitope accessibility. Overnight staining can thus substantially improve the resolution, repeatability, and cost-effectiveness of high-parameter cytometry. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.

+view abstract Current protocols, PMID: 36373983

Open Access
Burton AR, Guillaume SM, Foster WS, Wheatley AK, Hill DL, Carr EJ, Linterman MA Immunology

Influenza infection imparts an age-related increase in mortality and morbidity. The most effective countermeasure is vaccination; however, vaccines offer modest protection in older adults. To investigate how aging impacts the memory B cell response, we track hemagglutinin-specific B cells by indexed flow sorting and single-cell RNA sequencing (scRNA-seq) in 20 healthy adults that were administered the trivalent influenza vaccine. We demonstrate age-related skewing in the memory B cell compartment 6 weeks after vaccination, with younger adults developing hemagglutinin-specific memory B cells with an FcRL5 "atypical" phenotype, showing evidence of somatic hypermutation and positive selection, which happened to a lesser extent in older persons. We use publicly available scRNA-seq from paired human lymph node and blood samples to corroborate that FcRL5 atypical memory B cells can derive from germinal center (GC) precursors. Together, this study shows that the aged human GC reaction and memory B cell response following vaccination is defective.

+view abstract Cell reports, PMID: 36351385

Brailey PM, Evans L, López-Rodríguez JC, Sinadinos A, Tyrrel V, Kelly G, O'Donnell V, Ghazal P, John S, Barral P Signalling

Alterations in cellular metabolism underpin macrophage activation, yet little is known regarding how key immunological molecules regulate metabolic programs in macrophages. Here we uncover a function for the antigen presenting molecule CD1d in the control of lipid metabolism. We show that CD1d-deficient macrophages exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import. This metabolic rewiring primes macrophages for enhanced responses to innate signals, as CD1d-KO cells show higher signalling and cytokine secretion upon Toll-like receptor stimulation. Mechanistically, CD1d modulates lipid import by controlling the internalization of the lipid transporter CD36, while blocking lipid uptake through CD36 restores metabolic and immune responses in macrophages. Thus, our data reveal CD1d as a key regulator of an inflammatory-metabolic circuit in macrophages, independent of its function in the control of T cell responses.

+view abstract Nature communications, PMID: 36344546

Lawson CD, Hornigold K, Pan D, Niewczas I, Andrews S, Clark J, Welch H Signalling,Bioinformatics

P-Rex1 and P-Rex2 are guanine-nucleotide exchange factors (GEFs) that activate Rac small GTPases in response to the stimulation of G protein-coupled receptors and phosphoinositide 3-kinase. P-Rex Rac-GEFs regulate the morphology, adhesion and migration of various cell types, as well as reactive oxygen species production and cell cycle progression. P-Rex Rac-GEFs also have pathogenic roles in the initiation, progression or metastasis of several types of cancer. With one exception, all P-Rex functions are known or assumed to be mediated through their catalytic Rac-GEF activity. Thus, inhibitors of P-Rex Rac-GEF activity would be valuable research tools. We have generated a panel of small-molecule P-Rex inhibitors that target the interface between the catalytic DH domain of P-Rex Rac-GEFs and Rac. Our best-characterized compound, P-Rex inhibitor 1 (PREX-in1), blocks the Rac-GEF activity of full-length P-Rex1 and P-Rex2, and of their isolated catalytic domains, at low-micromolar concentration, without affecting the activities of several other Rho-GEFs. PREX-in1 blocks the P-Rex1 dependent spreading of PDGF-stimulated endothelial cells and the production of reactive oxygen species in fMLP-stimulated mouse neutrophils. Structure-function analysis revealed critical structural elements of PREX-in1, allowing us to develop derivatives with increased efficacy, the best with an IC of 2 µM. In summary, we have developed PREX-in1 and derivative small-molecule compounds that will be useful laboratory research tools for the study of P-Rex function. These compounds may also be a good starting point for the future development of more sophisticated drug-like inhibitors aimed at targeting P-Rex Rac-GEFs in cancer.

+view abstract Small GTPases, PMID: 36342857

Open Access
Orozco G, Schoenfelder S, Walker N, Eyre S, Fraser P Epigenetics

Genome sequencing has revealed over 300 million genetic variations in human populations. Over 90% of variants are single nucleotide polymorphisms (SNPs), the remainder include short deletions or insertions, and small numbers of structural variants. Hundreds of thousands of these variants have been associated with specific phenotypic traits and diseases through genome wide association studies which link significant differences in variant frequencies with specific phenotypes among large groups of individuals. Only 5% of disease-associated SNPs are located in gene coding sequences, with the potential to disrupt gene expression or alter of the function of encoded proteins. The remaining 95% of disease-associated SNPs are located in non-coding DNA sequences which make up 98% of the genome. The role of non-coding, disease-associated SNPs, many of which are located at considerable distances from any gene, was at first a mystery until the discovery that gene promoters regularly interact with distal regulatory elements to control gene expression. Disease-associated SNPs are enriched at the millions of gene regulatory elements that are dispersed throughout the non-coding sequences of the genome, suggesting they function as gene regulation variants. Assigning specific regulatory elements to the genes they control is not straightforward since they can be millions of base pairs apart. In this review we describe how understanding 3D genome organization can identify specific interactions between gene promoters and distal regulatory elements and how 3D genomics can link disease-associated SNPs to their target genes. Understanding which gene or genes contribute to a specific disease is the first step in designing rational therapeutic interventions.

+view abstract Frontiers in cell and developmental biology, PMID: 36340032

Liston A Immunology

No abstract available

+view abstract Immunology and cell biology, PMID: 36317807