BioNut internal seminars
Are you aware of what your colleagues work on, next door or one floor up? Did you know that BioNut has very diverse research fields, about 30 research groups and 4 core facilities?
Now you get a chance to learn what expertise you can find right here at your door step! All it takes is 1h twice per month and free sandwiches are served! The Internal seminar series at BioNut opens the door to new discussions and potential collaborations. PhD students who come regularly will even get credits!
Three speakers from different labs at BioNut present their work for 15 min each (+ questions)
Time and place:
Every second week on Thursdays from 11:30 to 12:30, in the red seminar room located near the C staircase on the 6th floor. The abstract for each speaker will be send by email to everyone at BioNut a couple of days before the seminar.
PhD students after their half time seminars and postdocs who have worked at BioNut more than 6 months.
Join the internal seminars! This is a great opportunity to start new collaborations, get help from your colleagues and broaden your knowledge!
Speakers 11/5 -2017
Jianjiang Hu: Explore the relationship of GTPase activity and traction force in single cell migration
Background: Small GTPases play important roles in regulating cell migration while traction force achieves it.
Results: Microscopy aided simultaneous observation of the spatiotemporal changes of GTPase activity (FRET based) and traction force during cell migration has been established. Acquired data is undergoing extensive analysis.
Conclusions: RhoA and Rac1 display positive correlation with traction force at the subcellular level.
Significance: Our established method could reveal interactions between different GTPase activities and traction force during cell migration.
A versatile toolkit to produce sensitive FRET biosensors to visualize signaling in time and space.
Sci Signal 2013 Jul;6(285):rs12
Stresses at the cell-to-substrate interface during locomotion of fibroblasts.
Biophys. J. 1999 Apr;76(4):2307-16
Muhammad Kashif: Defining the role of antioxidants in malignant melanoma metastasis
Background: We found that antioxidants increase lung cancer and malignant melanoma metastasis in vivo and the invasion and migration of cultured human cancer cells. The results raised several new questions.
Results: High throughput screening of redox compounds identified one group of compounds that accelerated and another that blocked migration of human melanoma cells. We will determine the compounds’ effect on ROS levels in cells and whether they can sensitize the cells to chemotherapeutic drugs.
Conclusion: We have exciting preliminary data that will be explored further.
Significance: Our data suggest that ROS limits the ability of cancer cells to metastasize. We will explore mechanisms behind this new finding and determine if redox-related weaknesses of cancer cells can be exploited for therapeutic purposes.
Speakers 27/4 -2017
Jana Lalakova: Exploring the role of centrosome inheritance in human stem-like cells (SLCs)
Background: Each cell cycle, the centrosome duplicates to form two centrosomes that differ in age, structure and composition. Old and new centrosomes are non-randomly inherited in asymmetrically dividing stem cells from different model organisms, where centrosome age is coupled to cell fate. However, whether such connection exists in human stem cells and what is the molecular link between centrosome age and cell fate remain unknown.
Results: In collaboration with Katajisto lab, we have developed a system to follow the inheritance of centrosomes in SLCs by fluorescence microscopy and flow cytometry. We are currently using this tool in combination with mammosphere assays to determine if centrosome inheritance correlates with stemness properties. Our long-term goal is to exploit this system to identify stem-cell specific components associated with old/new centrosomes.
Significance: Our work has a potential to elucidate fundamental mechanisms of stemness maintenance and proliferation of cancer stem cells, and may result in the identification of new molecular targets for cancer therapy.
When fate follows age: unequal centrosomes in asymmetric cell division.
Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2014 Sep;369(1650):
Tomas McKenna: Effects of ECM signalling and restricted cell attachment on stem cells
Stem cells reside in tissue specific niches featuring complex mechanical and biochemical properties, such as stiffness or ECM-bound growth factors and ligands. By separately controlling both the ECM composition and attachment area we can examine the effects of spatially restricted specific basement membrane proteins on stemness.
Our findings show that the stem cell niche controls stem cell behaviour with spatially and temporally specific laminin expression.
Extracellular-matrix tethering regulates stem-cell fate.
Nat Mater 2012 May;11(7):642-9
Peter Vrtacnik: The effect of a high somatic mutation burden in satellite cells on muscle regeneration
Background: Somatic mutation burden continuously increases with age in normal tissues.
Results: Skeletal muscle progenitor cells are also subjected to age-related accumulation of somatic mutations despite their quiescent nature.
Conclusions: Using DNA repair-deficient animal models we are evaluating whether accumulated somatic mutations can cause skeletal muscle disfunction.
Significance: Identifying the molecular drivers of aging is essential for our understanding of age-related tissue degeneration and disease onset.
The origin and evolution of mutations in acute myeloid leukemia.
Cell 2012 Jul;150(2):264-78
Speakers 16/3 -2017
Ani Azatyan: Mechanisms acting on Hedgehog signaling and their therapeutic potential.
Background: Inappropriate activation of Hedgehog-GLI signaling is involved in various cancers and signaling antagonists are anticipated to have significant clinical implications.
Results: RITA (reactivation of p53 and induction of tumor cell apoptosis) downregulates Hedgehog-GLI signaling in medulloblastoma and rhabdomyosarcoma cells in a JNK-dependent, but p53-independent manner.
Conclusions: RITA can sensitize cells to GANT61 (GLI antagonist 61) treatment, as co-administration of these drugs had synergistic or additive effects on cell proliferation and apoptosis.
Significance: RITA and GANT61 combinatorial treatment may additively/synergistically suppress Hedgehog-activated tumors in vivo, allowing the application of lower doses.
Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy.
Dev. Cell 2016 08;38(4):333-44
Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors.
Nat. Med. 2004 Dec;10(12):1321-8
Maria Henström: Genetics of irritable bowel syndrome and associated gastrointestinal symptoms
Background: Irritable bowel syndrome (IBS) is a common but complex gut disorder with unknown pathophysiology.
Results: We perform candidate-gene studies (e.g. Henström et al 2016) as well as large-scale GWASs for the discovery of IBS risk genes/variants.
Conclusions: By adopting different approaches we begin to identify risk gene candidates for further investigation.
Significance: Better understanding of the underlying IBS pathophysiology. Eventually improved diagnostics, sub-classifications and therapy.
Key reference: Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Gut 2018 Feb;67(2):263-270
Speakers 16/2 -2017
Sara Göransson: The role of matrix stiffness in breast cancer progression
Background: Extracellular matrix stiffness is increasingly recognized as an important contributor to breast tumor progression
Results: Proteomic analysis of breast cancer cells cultured on different stiffness revealed that proteins of the Mevalonate pathway are up-regulated on higher stiffness
Conclusions: Our finding establishes a link between a well known metabolic pathway and matrix stiffness
Significance: The efficacy of Statins, drugs that inhibit the Mevalonate pathway, as anti-tumor agents might depend on the tumor microenvironment
From transformation to metastasis: deconstructing the extracellular matrix in breast cancer.
Cancer Metastasis Rev. 2016 Dec;35(4):655-667
Mullen PJ, Yu R, Longo J, Archer MC & Penn LZ. The interplay between cell signaling and the mevalonate pathway in cancer. Nature Rev Cancer (2016) 16: 718. doi:10.1038/nrc.2016.76
Uta Rabenhorst: Development of Hedgehog pathway inhibitors directly targeting the transcription factor Gli
Background: Due to the involvement of Hedgehog signaling in various types of cancer, pathway inhibitors are being developed for clinical use.
Results: Cell-based screening of small molecules led to identification of potent hedgehog inhibitors. But in validation experiments these inhibitors showed broad non-specific effects.
Conclusions: The identified hedgehog inhibitors are not suitable for further development.
Significance: Patients treated with existing hedgehog inhibitors develop resistance, therefore alternative compounds are urgently needed.
Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy.
Dev. Cell 2016 08;38(4):333-44
Amakye, D, Jagani, Z & Dorsch, M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nature Medicine 19, 1410–1422 (2013). doi:10.1038/nm.3389
Enrichetta Mileti "Adipose gene expression in non obese and obese who are discordant in insulin response"
Background: Metabolically healthy obese subjects display preserved insulin sensitivity and a beneficial adipose tissue gene expression.
Results: There was an overall expression response in obese insulin sensitive (ISO) and insulin resistant (IRO), as well as non-obese (NO) subjects.
Conclusions: ISO and IRO displayed a similar transcriptional response to insulin, which differed from the small effect observed in NO.
Significance: This study demonstrates that differences in transcriptional response are primarily driven by obesity per se, challenging the notion of healthy obese.
The Adipose Transcriptional Response to Insulin Is Determined by Obesity, Not Insulin Sensitivity.
Cell Rep 2016 08;16(9):2317-26
Speakers 2/2 -2017
Marco Gerling: Stromal Hedgehog signaling in gastrointestinal cancer and metastases
Background: Activation of Hedgehog signaling has been proposed to shape a tumor-promoting stroma in several types of cancer, but clinical trials with Hedgehog antagonists were discouraging.
Results: We studied Hedgehog signaling in mouse models of colon cancer and found that Hedgehog targets are exclusively expressed in the stroma and that activation of Hedgehog restricts tumor growth.
Conclusion: Genes regulated by hedgehog hold potential as stroma-derived therapeutic targets, while Hedgehog inhibition contrarily might pose patients at risk for the development of solid malignancies.
Significance: Our results highlight the potential of stroma cells to restrain tumor growth and suggest that stromal Hedgehog targets may be exploited with therapeutic benefit.
Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth.
Nat Commun 2016 Aug;7():12321
Control of inflammation by stromal Hedgehog pathway activation restrains colitis.
Proc. Natl. Acad. Sci. U.S.A. 2016 Nov;113(47):E7545-E7553
Christine Delisle Nyström: Mobile-based intervention intended to stop obesity in pre-school children: The MINISTOP randomized controlled trial
Background: Mobile phone technology (mHealth) has been successful for behavior change and weight management in adults, however, its potential in young children has yet to be examined.
Results: The intervention group (n = 155) significantly increased their average composite score (made up of body fatness, dietary, and physical activity variables) from baseline to follow-up, whereas the control group (n = 158) did not, with the effects being more pronounced in the children with a higher fat mass index.
Conclusions: Our findings suggest that mHealth may be able to aid parents in improving obesity markers in young children.
Significance: As mHealth is easily adaptable and relatively inexpensive this may be a feasible method to implement within the ordinary child healthcare system to aid parents in preventing obesity in their pre-school aged children.
Mobile Phone Apps to Promote Weight Loss and Increase Physical Activity: A Systematic Review and Meta-Analysis.
J. Med. Internet Res. 2015 Nov;17(11):e253
Interventions for preventing obesity in children.
Cochrane Database Syst Rev 2011 Dec;(12):CD001871
Sophia Miliara: Insights into the role of mutant Nucleophosmin in Acute Myeloid Leukemia
Background: Nucleophosmin is a nucleolar, multifunctional protein, which is the most frequently mutated gene in Acute Myeloid Leukemia (AML). Mutant nucleophosmin is translocalized to the cytoplasm.
Results and conclusion: A major binding partner of nucleophosmin is also found to be translocated to the cytoplasm, possibly resulting in nucleolar stress.
Significance: Elucidation of the mechanism, underlying cytoplasmic translocalization of Nucleophosmin binding partners can lead to better treatments for AML.
NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling.
Biochem Res Int 2011 ;2011():195209
Speakers 15/12 -2016
Serena Barilla: Epigenomic control of adipocytes fate and function by the obesity-regulated coregulator GPS2
Background: The rising prevalence of obesity and diabetes has increased the interest in adipose tissue biology and its therapeutic potential.
Results: Adipocytes-specific GPS2 knockout mice display white adipocytes hypertrophy and epigenomic changes are observed in GPS2 depleted 3T3-L1 cells.
Conclusion: GPS2 modulates adipocytes differentiation and metabolism in a differentiation-stage specific manner.
Significance: The elucidation of GPS2 role in adipocytes biology appears relevant for the modulation of the characteristic excessive accumulation of adipose tissue in obesity.
SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation.
J. Clin. Invest. 2013 Jan;123(1):362-79
Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes.
Nat. Med. 2016 07;22(7):780-91
Isha Ray: Structural basis of species specific egg-sperm recognition at fertilization
Background: The gamete recognition proteins in the mollusk abalone, sperm lysin and multivalent protein VERL (Vitelline Envelope Receptor for Lysin), interact in species-specific manner to facilitate fertilization.
Results and conclusion: We evaluated binding between lysin and various VERL repeats. It was found that species specificity in abalone is regulated by a complex interplay between different repeats of VERL.
Significance: This work reveals how gametes interact and how species specificity is regulated at a molecular level.
Interspecies chimeric sperm lysins identify regions mediating species-specific recognition of the abalone egg vitelline envelope.
Dev. Biol. 1999 Oct;214(1):151-9
The molecular basis of sex: linking yeast to human.
Mol. Biol. Evol. 2011 Jul;28(7):1963-6
Speakers 1/12 -2016
Gwladys Revechon: Rare progerin-expressing preadipocytes and adipocytes results in tissue depletion over time
Background: Several studies have revealed the presence of progerin (the protein responsible progeria) in normal human tissues; however its significance has been debated.
Results: Sustained low frequency of progerin-positive cells in mice adipose tissue leads to early senescence and DNA damage accumulation, thus resulting in tissue depletion with increased age.
Conclusion: Our findings suggest that the adipose tissue is highly sensitive to progerin expression.
Significance: Our results emphasize progerin’s possible causal role in certain tissue alterations during normal aging.
DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria.
Cell Metab. 2013 Sep;18(3):403-15
Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.
Nature 2016 Feb;530(7589):184-9
Lee Siggens: Aberrant DNA methylation in Acute Myeloid Leukaemia reveals silencing and activation of enhancers
Background: DNA methylation is altered in acute myeloid leukaemia (AML).
Results: Sites of differential methylation occur primarily in regulatory elements including enhancers, which become silenced or activated in cancer.
Conclusion: The enhancer network is rewired in AML at sites of aberrant DNA methylation.
Significance: We need to develop therapies, which can restore silenced or activated enhancers to their natural state in blood cells to better treat AML.
DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.
Cancer Cell 2010 Jan;17(1):13-27
Speakers 17/11 -2016
Matthias Spiess: Distinct nano-organization of active and inactive β1-integrins within focal adhesions
Background: Cell-matrix adhesion complexes (e.g. focal adhesions), mediated by integrin transmembrane adhesion receptors, play critical roles in physiology and disease.
Results: We identify active integrin nanoclusters aligning to form linear structures within focal adhesions while inactive β1 integrin nanoclusters are less organized and more dispersed within adhesions.
Conclusion: The identification of distinct active and inactive integrin nanocluster suggests a nano-organization and a coordinate mechanism of integrin activation within focal adhesions.
Significance: We provide novel insights into the nano-architecture of focal adhesions and the molecular underpinning of the adhesion complexes.
Nanoscale architecture of integrin-based cell adhesions.
Nature 2010 Nov;468(7323):580-4
Dissecting the molecular architecture of integrin adhesion sites by cryo-electron tomography.
Nat. Cell Biol. 2010 Sep;12(9):909-15
Marika Sjöqvist: Degeneralizing Notch – Paralog-specific characteristics of Notch signaling
Background: Alagille syndrome is a multi-organ dysfunction disorder caused by mutations in the Notch ligand Jagged1. The precise molecular mechanisms causing various symptoms in Alagille syndrome are still unclear.
Results: A mutated form of Jagged1 (called Nodder, “Ndr”) shows reduced capacity to interact with Notch1 and Notch3, whereas the interaction with Notch2 appears almost unaffected by the mutation.
Conclusion: Jagged1 signaling through individual Notch receptors is differentially affected by the Ndr mutation.
Significance: Our data describes the first mutation on the Notch ligand Jagged1 that discriminates between different Notch receptor paralogs. This finding may be crucial for understanding and eventually developing therapies for some of the varying symptoms observed in AGS patients.
Control of Notch-ligand endocytosis by ligand-receptor interaction.
J. Cell. Sci. 2010 Sep;123(Pt 17):2931-42
Hafdís Helgadóttir: Somatic lamin A mutations that result in progerin splicing in chronic kidney disease
Background: Similar premature vascular aging is seen in children with Hutchinson-Gilford progeria (HGPS) as in patients with chronic kidney disease (CKD). HGPS is caused by mutations in LMNA gene that lead to progerin (truncated protein)splicing in chronic kidney disease.
Results: 70% of CKD patients express progerin in the arterial media. Two somatic mutations were more common in blood DNA from CKD compared to controls.
Conclusion: Certain somatic mutations become a serious risk when increased regeneration is induced by extensive tissue damage as in CKD.
Significance: Novel mechanistic insight into the underlying phenotype of premature vascular aging.
Chronic kidney disease and premature ageing.
Nat Rev Nephrol 2014 Dec;10(12):732-42
Speakers 3/11 -2016
Kashyap Dave: Delineating MYC enhancers in gene regulation and tumor development
Background: MYC is well known oncogene and its deregulated expression directly contributes to malignant transformation in various cell types.
Results: In vivo deletion of enhancers up upstream of the MYC oncogene in mice results in 50 to 80% decrease in MYC expression in multiple tissues. It does not affect normal growth in mice.
Conclusion: Enhancers acts as gene switches that regulate MYC expression and growth during tumor development.
Significance: Such cancer specific enhancer elements may serve as new attractive targets for cancer therapeutics.
Key reference: Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors.
Science 2012 Dec;338(6112):1360-3
Jingwen Wang: Identification of Novel Transcribed Regions in Zebrafish
Background: Zebrafish has emerged as a model organism to investigate vertebrate development and human genetic diseases. However the zebrafish genome annotation is still on going and not complete.
Results: We identified more than 150 new transcribed regions (NTRs) in zebrafish genome using RNA sequencing data, and performed validation or functional studies on certain selected NTRs.
Conclusion: We provided new information for genome characterisation of the model organism zebrafish.
Significance: A more complete annotation of zebrafish genome increases the value of the zebrafish for studying the function of disease causative genes.
Zebrafish mRNA sequencing deciphers novelties in transcriptome dynamics during maternal to zygotic transition.
Genome Res. 2011 Aug;21(8):1328-38
The zebrafish transcriptome during early development.
BMC Dev. Biol. 2011 May;11():30
Speakers 13/10 -2016
Tahmina Akhter: Analysis of biomarkers and phenotypes in asthma and COPD
Background: Asthma and chronic obstructive pulmonary diseases (COPD) are highly prevalent lung diseases worldwide. They are characterized by chronic airways obstruction and airways inflammation.
Results: Found biomarkers linked with the asthma and COPD.
Conclusion: These biomarkers showed significant effects of drug in asthma and COPD in different time points.
Significance: These biomarkers could use in drug development for asthma and COPD.
Key reference: Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma.
Allergy 2014 Sep;69(9):1198-204
Nancy Yu: Short term effects of physiological consumption levels of caffeine on iPSC-derived neurons
Background: We performed a gene expression profiling study on the effects of caffeine on iPSC-derived neurons.
Results: Axon guidance genes were perturbed 1-3 hours after the addition of 10μM caffeine.
Conclusion: Caffeine has an observable effect on expression levels of neuronal projection processes.
Significance: This work may be a first step towards elucidating the molecular mechanisms of caffeine’s effects on learning and memory formation.
Key reference: Human embryonic stem cell proliferation and differentiation as parameters to evaluate developmental toxicity.
J. Cell. Physiol. 2011 Jun;226(6):1583-95
Speakers 29/9 -2016
Tânia Costa: PAK4 controls the non-canonical NFkB component RelB to prevent senescence-like growth arrest in breast cancer
Background: PAK4 is frequently overexpressed in tumours and contributes to multiple hallmarks of cancer.
Results: PAK4 inhibition induces senescence-like features in multiple in vitro, in vivo and ex vivo cancer models.
Conclusion: PAK4 is a pro-tumourigenic regulator of breast cancer acting through the non-canonical NFkB subunit RelB.
Significance: Cancer cells are vulnerable to PAK4 inhibition and this may be explored as a therapeutic strategy.
Key reference: PAK signalling during the development and progression of cancer.
Nat. Rev. Cancer 2014 Jan;14(1):13-25
Rongrong Fan: Epigenomic regulatory mechanism of GPS2 in meta-flammation
Background: Epigenomic alterations regulates macrophage inflammation upon metabolic stress contributes to development of obesity induced insulin resistance and type 2 diabetes.
Results and conclusion: We identified GPS2 as a crucial epigenomic brake which inhibits macrophage metaflammation and alleviates progression of obesity induced type 2 diabetes in both mice and humans.
Significance: The study increased understanding of epigenomic regulatory mechanisms during progressive metaflammationin obesity patients.
Key reference: Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes.
Nat. Med. 2016 07;22(7):780-91
Ning Liang: Epigenetic control of hepatic lipid metabolism by GPS2-complex
Background: GPS2-containing corepressor complex modulates epigenomic regulation of lipid metabolism and inflammation via interplaying with multiple transcription factors in various metabolic tissues. Hepatic lipid metabolism is highly associated with metabolic disorders (such as liver steatosis and atherosclerosis).
Results and conclusion: GPS2 liver KO mice showed lowered serum VLDL triglyceride, improved liver steatosis and insulin sensitivity in obesity mice models, which is potentially linked to derepressed PPARa activity and FGF21 expression.
Significance: We proposed a lipid regulatory mechanism by GPS2. Further understanding of the epigenomic regulation of hepatic lipid metabolism is ultimately needed to develop efficacious interventions.
Key reference: Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor.
Mol. Cell 2013 Dec;52(6):769-82
Aiman Elmansuri: Is Notch an oncogene or a tumor suppressor in liver?
Background: The role of the Notch signaling pathway is controversial in liver cancer. Here, we investigate the Jagged1 ligand-Notch receptor interactions and their consequent influence on liver tumorigenesis.
Results: Jaged1 point mutant mice (Jag1Ndr/Ndr) do not develop liver tumors, in contrast to the wild types in a genetic background predicsposed to liver tumors. Luciferase assays show that JagNdr cells are capable of activating Notch2 receptors, but not Notch1 or Notch3.
Conclusion: Liver tumor development probably proceeds through Jag1-Notch1 or Jag1-Notch3 dependent pathway.
Significance: This will allow us to design more effective Notch based therapies for liver malignancies.
Differential effects of targeting Notch receptors in a mouse model of liver cancer.
Hepatology 2015 Mar;61(3):942-52
Control of Notch-ligand endocytosis by ligand-receptor interaction.
J. Cell. Sci. 2010 Sep;123(Pt 17):2931-42
Debora Sugiaman-Trapman: The Role of RFX transcription factors in development and disease
Background: Dimeric RFX transcription factors (TFs) bind conserved X-box promoter motif.
Results: We provide a comprehensive survey on eight human RFX TFs.
Conclusion: There is a commonality in the role of RFX TFs through their targets at polarised cell surfaces, e.g. cilia and synapse.
Significance: We have deeper understanding on human RFX TFs, their role in developmental biology and ciliopathy disease states in humans, e.g. developmental dyslexia.
Key references: [pubmed:18673564]
Fatemeh Hadizadeh: A genome-wide study of the impact of human genetic variation on gut microbiota composition
Background: Host genetic make-up may play a role in shaping gut microbiota composition.
Results: Regression analyses identified a number of signals with suggestive association.
Conclusion: Carbohydrate and unsaturated fatty acid metabolism showed significant association with gut microbiota composition.
Significance: These results may contribute to provide more insights into the mechanisms involved in the formation of gut microbiota composition.
Key reference: [pubmed:26374288]
Wenbo Dong: A Study of functional roles of different domains in hrp3 during the process of chromatin remodeling
Background: Chromatin remodeling enzyme CHD1 is important for maintaining the open structure of chromatin and involves in transcription elongation. It has two orthologues in S.pombe, Hrp3 and Hrp1. Hrp3 functions in a very different way compare to Hrp1.
Results: Deletions of different domains in Hrp3 can affect aspects including histone binding, and the ability of hydrolyzing ATP etc.
Conclusion: In this study, we are trying to reveal the roles of each domain in Hrp3 and finally identify how they work together during the process of remodeling.
Significance: This study reveals the basic mechanism of Hrp3 for chromatin remodeling. It can also help to give explanation for functional mechanism of CHD1 in human.
Key reference: CHD1 remodelers regulate nucleosome spacing in vitro and align nucleosomal arrays over gene coding regions in S. pombe.
EMBO J. 2012 Nov;31(23):4388-403
Romina Croci: Expression and Purification of GLI1-SUFU complex for structural studies
Background: Transcription Factors GLIs and their regulator protein SUFU have a crucial rule in the Hedgehog signaling pathway, involved in embryonic development and tumorigenesis. The way they interact each other is still unclear.
Results: Seven different SUFU-GLI complexes have been tested (different GLI constructs) and several crystal screenings have been set up without any significant results yet.
Conclusion: GLI protein is likely partially unfolded and this prevents the crystals growth. To study the complex structure other techniques have to be considered (e.g. Cryo-EM).
Significance: Biochemical and structural characterizations of SUFU-GLI complex are essential for the further understanding of the Hedgehog pathway and the rational design of drugs that can block the onset of cancers.
Key reference: Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation.
Acta Crystallogr. D Biol. Crystallogr. 2013 Dec;69(Pt 12):2563-79
Yossa Dwi Hartono: Characterisation of base-opening in nucleic acid triplexes by umbrella sampling and lambda dynamics
Background: Nucleic acid triplexes are important in gene-targetting procedures, but lack biophysical characterisations.
Results: Umbrella sampling along the pathway of base opening is done with various bases and sugars.
Conclusion: Certain sugars and bases as well as sequence context yield different energy profiles of base-opening in nucleic acid triplexes.
Significance: Quantification and characterisation of base-opening reaction can guide design of sequence as well as modified bases and sugars for better gene-targetting procedures.
Key reference: Proton exchange and base pair opening in a DNA triple helix.
Biochemistry 2001 Sep;40(37):11065-72
Zhiqiang Huang: Loss of corepressor GPS2 sensitizes macrophage activation upon metabolic stress in obesity and type-2 diabetes
Background: Inflammatory cells, including monocyte-macrophage lineage, can develop into phenotypically distinct subpopulation in function of the microenvironment.
Results: GPS2-deficient macrophages display pro-inflammatory signatures resembling toll-like receptor activation, including elevated monocyte chemoattractant protein-1, and hypersensitivity towards infectious and metabolic signals. GPS2 occupies H3K27ac-marked enhancers and promoters, which upon GPS2 removal undergo epigenomic alterations linked to transcription.
Conclusion: Studies of obesity mouse models and obese/diabetic human subjects reveal a causal relationship between inappropriate GPS2 expression and function, adipose tissue inflammation, and insulin resistance. Thus, corepressor-dependent epigenomic mechanisms in macrophages control the inflammatory response to metabolic activation.
Significance: Thus, our study reveals a potentially reversible disease mechanism that links corepressor-dependent epigenomic alterations in macrophages to adipose tissue inflammation and the development of insulin resistance and diabetes.
Key reference: Rongrong Fan, et al. Loss of corepressor GPS2 sensitizes macrophage activation upon metabolic stress in obesity and type-2 diabetes. Nature Medicine (accepted paper)
Jiyu Guan: Microenvironment-mediated BTK inhibitor Ibrutinib resistance in Mantle cell lymphoma is overcome by PI3K inhibition
Background: Microenvironment is important to support tumor survival and progression.
Results: Stroma promotes MCL tumor growth and prevents MCL tumor from undergoing apoptosis following treatment with BTK inhibitor ibrutinib by upregulating PI3K/AKT signaling.
Conclusion: Targeting MCL with Ibrutinib is facing microenvironment-mediated resistance.
Significance: We demonstrate a non-cell-autonomous ibrutinib resistance mechanism in MCL therapy that may be overcome by PI3K/AKT inhibition.
Key reference: The tumour microenvironment in B cell lymphomas.
Nat. Rev. Cancer 2014 Aug;14(8):517-34
Katja Frühauf: 4sU RNA labeling as tool for studying the genomic response to signaling pathways and/or general transcriptional mechanism
Background: The synthesis and decay of RNA transcripts are key mechanisms for the regulation of gene expression. 4sU RNA labeling allows the simultaneous measurement of RNA synthesis and decay rates.
Results: In this seminar I will present three stories in which 4sU RNA labeling was applied to study 1) Innate immune response in bone marrow derived primary mouse macrophages, 2) Steroid hormone signaling in Drosophila S2 cells and 3) The human transient transcriptome.
Conclusion: Expression profiling using 4sU RNA labeling has higher sensitivity and temporal resolution than standard transcriptomics. Furthermore, it captures transient non-coding RNAs, e.g. enhancer RNAs.
Significance: 4sU RNA labeling is a highly valuable tool for the analysis of gene-regulatory systems.
Key reference: Dynamic transcriptome analysis measures rates of mRNA synthesis and decay in yeast.
Mol. Syst. Biol. 2011 Jan;7():458
Rampradeep Samiappan: Structural analysis of transmembrane proteins stabilized by insertion into nanodiscs
Background: Interaction studies of sodium-potassium pump (Na+, K+- ATPase) with one or more interaction partners at structural and functional levels to understand the physiological functions of the enzyme.
Results: Insertion of Na+, K+-ATPase in nanodiscs and validation of the same is completed.
Conclusion: Nanodiscs enables visualization of relatively small transmembrane proteins by Cryo EM and native PAGE.
Significance: Besides the physiological significance of Na+, K+- ATPase, a comprehensive understanding of Na+, K+-ATPase signaling would add another dimension to this fascinating enzyme and open the field for future interdisciplinary studies.
Key reference: Na(+),K (+)-ATPase as a docking station: protein-protein complexes of the Na(+),K (+)-ATPase.
Cell. Mol. Life Sci. 2013 Jan;70(2):205-22
Andrea Bieder: The role of dyslexia candidate genes in cilia
Background: Several dyslexia candidate genes (DCGs) are involved in neuronal migration and cilia.
Results: We have identified the DCG DCDC2 as a ciliopathy gene and we found that two of the DCGs are regulated by the ciliary RFX factors.
Conclusion: We provide additional evidence for a role of certain DCGs in cilia biology.
Significance: These studies might lead to a better understanding of the biological mechanisms behind dyslexia and ciliopathies.
Key reference: DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling.
Am. J. Hum. Genet. 2015 Jan;96(1):81-92
Mukesh Varshney: Role of Estrogen receptor beta in neural development and possible targets
Background: Estrogen receptor β is essential for proper corticogenesis during fetal life and it may modulate the activation of different targets important for proper neuronal development. These early events might play a role in neurodegenerative diseases.
Results: Lack of ERβ in mouse embryonic stem cells led to a decrease in neural progenitor cell (NPC) marker expression and delayed their further differentiation to dopaminergic neurons.
Conclusion: It is too early to derive conclusion with preliminary investigative analyses.
Significance: Understanding the neurodevelopmental patterns in the absence of ERβ will contribute to delineate the etiology of neurodegenerative disorder in later life.
Key reference: ERbeta in CNS: new roles in development and function.
Prog. Brain Res. 2010 ;181():233-50
Michael Lidschreiber: Widespread RNA interaction of transcription elongation factors
Background: Recent evidence suggests that RNA interaction can regulate the activity and localization of chromatin associated proteins.
Results: Here we mapped 13 transcription elongation factors (EFs) onto the yeast transcriptome using PAR-CLIP1. For ten of the EFs we detected high-confidence RNA interaction sites.
Conclusion: EFs differ in their binding preferences for distinct transcript classes and/or transcript regions, providing evidence that the observed RNA interactions are specific. Moreover, RNA stabilizes the chromatin association of these factors.
Significance: The presented transcriptome-wide binding maps will enable many future analyses to further dissect the role of RNA in regulating transcription elongation.
Key reference: Transcriptome maps of mRNP biogenesis factors define pre-mRNA recognition.
Mol. Cell 2014 Sep;55(5):745-57
Irene Franco: Analysis of somatic genetic variation during physiologic aging
Background: Progressive accumulation of somatic genetic modifications is considered a leading cause of cellular aging.
Results: To assess age-related somatic variability in human tissues, single stem cells were isolated from muscle, fat and kidney tissue from young and old individuals and clonally expanded. Multiple clones from the same tissue were subjected to whole genome sequencing and cell specific variants were analysed.
Conclusion: Analyses are too preliminary to drive conclusions.
Significance: These analyses will provide a characterization of somatic mutation processes occurring during aging in multiple human tissues.
Key reference: Genome instability and aging.
Annu. Rev. Physiol. 2013 ;75():645-68
Ferdinando Bonfiglio: Genome-wide association studies and meta-analyses of gastroesophageal reflux disease in 23403 Northern Europeans
Background: Genetic predisposition to gastroesophageal reflux disease (GERD) is suspected but gene-hunting efforts have been scarce.
Results: We report the first GWA studies of GERD and their meta-analysis in 23403 unrelated individuals from three independent population-based cohorts.
Conclusion: We detect 30 risk loci showing concordant risk directions in all cohorts and functional effects in relevant tissues.
Significance: We highlight genes, pathways and computationally-predicted effective drugs that provide further insights into GERD pathophysiology.
Key reference: Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett's esophagus, and gastroesophageal reflux.
J. Natl. Cancer Inst. 2013 Nov;105(22):1711-8
Simon Joost: Single-cell transcriptomics reveals that differentiation and spatial signatures shape epidermal heterogeneity
Background: The murine epidermis with its hair follicles represents an invaluable model system for tissue regeneration and stem cell research.
Results: We used single-cell RNA-seq to reveal how cellular heterogeneity of murine telogen epidermis is tuned at the transcriptional level.
Conclusion: Unbiased clustering of 1,422 single-cell transcriptomes revealed 25 known and novel populations of epidermal cells, which are the result of interplay between a spatial and a differentiation-related axis of gene expression.
Significance: This study provides the first unbiased and systematic view of transcriptional organization of an adult epithelial tissue and highlights how cellular heterogeneity can be orchestrated in vivo to assure tissue homeostasis.
Key reference: Quantitative single-cell RNA-seq with unique molecular identifiers.
Nat. Methods 2014 Feb;11(2):163-6
Lucia Bialešová: Epigenetic changes on the PLIN promoter can cause obesity development
Background: Epigenetic factors, e.g. DNA methylation, affect genome function, which may contribute to common human diseases.
Results: Obesity is associated with a large number of DMS (differentially methylated DNA sites).
Conclusion: DMS accompanied by differential expression in genes linked to fat cells metabolism may contribute to abdominal fat storage.
Significance: Our study may help to elucidate the DNA methylation process during obesity development.
Key reference: The epigenetic signature of subcutaneous fat cells is linked to altered expression of genes implicated in lipid metabolism in obese women.
Clin Epigenetics 2015 ;7():93
Harriet Nilsson: Supramolecular Topology by Packing and Release of Mucins, resting on D3 domain assembly; Importance for Mucus Formatio
Background: Altered expression of mucins is an important cause of inflammatory diseases of the epithelium.
Results: Mechanisms behind how mucins, through their N-terminals, build up a barrier were revealed.
Conclusion: Structural variation in various mucin complexes points to tissue specific functions and organization of the whole mucus gel.
Significance: Understanding the above mechanisms may be beneficial for selective treatments.
Key reference: Godl K, Johansson ME, Lidell ME, Mörgelin M, Karlsson H, Olson FJ, Gum JR Jr, Kim YS, Hansson GC. The N terminus of the MUC2 mucin forms trimers that are held together within a trypsin-resistant core fragment. J Biol Chem. 2002, Dec 6;277(49):47248-56.
Martina Jezowska: Enabling attachment of uptake enhancing entities to oligonucleotides by development of multiple choice linkers for 5’-multiple conjugation.
Background: Nucleic Acid Technology has a very strong impact on biomedicine nowadays, yet there are still some limitations when it comes to oligionucleotide therapy. The main problem is poor delivery to the site of action and lability of oligonuleotides in biological fluids of oligonucleotides.
Results: To address this problem we have prepared a multiple conjugation linker which should allow attachment of various uptake enhancing entities to oligonucleotides and to assist overcoming the delivery barriers.
Conclusion: A methodology for synthesis of such oligonucleotide has been developed and the constructs can now be evaluated in biological studies.
Significance: The unique features of our multiple conjugation linker allow the attachment of different functional entities to oligonucleotides which should assist in delivery of the drug to: 1) the desired organ, 2) through the cell membrane and 3) inside the cell nucleus.
Evdokiya Salamanova: Effects of change-of-function mutations on helical propensity in the intrinsically disordered τ1-core activation domain of the Glucocorticoid receptor.
Background: Glucocorticoid receptor (GR) is an intrinsically disordered protein in its N-terminus.
Results: We have investigated the effect of change-of-function point mutations in the t1-core transactivation domain in GR on the helical propensity using a model system.
Conclusion: Both Bioinformatics and MD methods show correlation between the charge-of-function and propensity for helical formation in the disordered region.
Significance: The change-of-function mutations can be related to structural alterations in GR with the help of in silico methods as powerful structure prediction tools.
Key reference: Almlöf T, Ford J, Gustafsson J A, Wright A P (1997) Role of hydrophobic amino acid clusters in the transactivation activity of the human glucocorticoid receptor. Mol Cell Biol, 17 (2):934-945
Yumei Diao: The Potential Role of GLI1 as Therapeutic Target for Tamoxifen-resistant Breast Cancer
Background: GLI1 is a major effector of Hedgehog (HH) signaling, potentiating signal activity. In 2012, Ramaswamy et al reported that HH signaling is activated by the PI3K/AKT pathway, bypassing the blockade of ER alpha signaling that was elicited by tamoxifen treatment.
Results: We find GLI1 is highly expressed in tamoxifen resistant cells compared to control cells, and ER alpha signaling activity is much stronger in tamoxifen resistant cells at basal level. Depletion of GLI1 decreases gene expression of ER alpha and its target genes, also reduces ER alpha signaling activity.
Conclusion: GLI1 may have a role in controlling tamoxifen resistance via modulation of ER alpha signaling.
Significance: Our unique combination of global proteomic methods provides a resource for further investigations on the role of PAK4 in physiology and disease.The mechanism of GLI1 modulating ER alpha signaling provides a clinical implication for ongoing investigations of anti-HH inhibitors in tamoxifen resistant breast cancer therapy.
Key Reference: Ramaswamy B, Lu Y, Teng KY, Nuovo G, Li X, Shapiro CL, Majumder S: Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res 2012, 72(19):5048-5059
Xiaoyan Sun: Study on the epidermal fate switching of hair follicle stem cells in response to injury
Background: Upon wounding, distinct skin stem cells (SCs) within hair follicles exit the follicles and participate in rapid wound re-epithelialization. However, the migratory factors necessary for epidermal fate switching of hair follicle SCs are not yet known.
Results: We combined cell lineage tracing technique, full-thickness excisional wound with various exogenous treatments to explore the migratory factors that trigger coordinated SC fate switching towards an interfollicular epidermal (IFE) lineage at the onset of wound healing.
Conclusion: We have confirmed that the molecular events in the first 24 hours post-wounding are responsible for the recruitment of hair follicle cells to the IFE. We are exploring now the major cell type and relevant signaling cascades.
Significance: This study will help better understand the nature of the wound microenvironment as well as the interplay among epidermal and dermal cells, all of which will provide important clues for skin tumor induction.
Key reference: Brownell, I., Guevara, E., Bai, C. B., Loomis, C. A., & Joyner, A. L. (2011). Nerve-Derived Sonic Hedgehog Defines a Niche for Hair Follicle Stem Cells Capable of Becoming Epidermal Stem Cells. Cell Stem Cell, 8(5), 552–565.
Ning Wang: Modulation of DNA methylation via CRISPR/dCas9 fusions
Background: DNA methylation is important for regulating gene expression in both normal development and disease, by using newly developed CRISPR/cas9 system, we aim to modulate DNA methylation in specific genomic regions.
Results: Several CpG sites within targeted locations were methylated or demethylated by transfection of CRISPR/dCas9 fusions in vitro.
Conclusions: Several CpG sites within targeted locations were methylated or demethylated by transfection of CRISPR/dCas9 fusions in vitro.
Significance: Artificial ribonucleases can be developed to valuable tools in biological/medical research and for diagnostics and/or treatment of diseases.
Key reference: Konermann S, Brigham MD, Trevino AE, Joung J, Abudayyeh OO, Barcena C, Hsu PD, Habib N, Gootenberg JS, Nishimasu H, Nureki O, Zhang F. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature. 2015 Jan 29;517(7536):583-8
Information to speakers
Format: 15 minutes presentation, 5 minutes discussion (please ensure that your presentation does not exceed the 15 minutes limit, aim at no more than 15 slides).
Requirements: All speakers should provide to Sylvie Le Guyader (who is acting as a co-host of the series) and Carsten Daub at least a week in advance a title, a key reference and an abstract of the presentation.
The abstract should be in the form of a “Capsule” as highlighted in the Journal of Biological Chemistry. (Please browse recently published JBC articles to see examples) “A Capsule should have 60 words or less and four parts that communicate the following to readers of all levels of interest and expertise:
Background: A complete sentence that explains the impetus and context of the work.
Results: A complete sentence that summarizes the major findings.
Conclusion: A complete sentence that summarizes the interpretation of the findings.
Significance: A complete sentence about the paper's impact on the field and its long-term implications.