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News Article | May 4, 2017
Site: www.eurekalert.org

A new study in Science from Karolinska Institutet maps out how different DNA-binding proteins in human cells react to certain biochemical modifications of the DNA molecule. The scientists report that some 'master' regulatory proteins can activate regions of the genome that are normally inactive due to epigenetic changes. Their findings contribute to a better understanding of gene regulation, embryonic development and the processes leading to diseases such as cancer. The DNA molecule carries information in the form of a sequence of four nucleotide bases, adenine (A), cytosine (C), guanine (G) and thymine (T), which can be thought of as the letters of the genomic language. Short sequences of the letters form 'DNA words' that determine when and where proteins are made in the body. Almost all of the cells in the human body contain the letters in precisely the same order. Different genes are however active (expressed) in different cell types, allowing the cells to function in their specialised roles, for example as a brain cell or a muscle cell. The key to this gene regulation lies in specialised DNA-binding proteins -- transcription factors -- that bind to the sequences and activate or repress gene activity. The DNA letter C exists in two forms, cytosine and methylcytosine, which can be thought of as the same letter with and without an accent (C and Ç). Methylation of DNA bases is a type of epigenetic modification, a biochemical change in the genome that does not alter the DNA sequence. The two variants of C have no effect on the kind of proteins that can be made, but they can have a major influence on when and where the proteins are produced. Previous research has shown that genomic regions where C is methylated are commonly inactive, and that many transcription factors are unable to bind to sequences that contain the methylated Ç. By analysing hundreds of different human transcription factors, researchers at Karolinska Institutet in Sweden have now found that certain transcription factors actually prefer the methylated Ç. These include transcription factors that are important in embryonic development, and for the development of prostate and colorectal cancers. "The results suggest that such 'master' regulatory factors could activate regions of the genome that are normally inactive, leading to the formation of organs during development, or the initiation of pathological changes in cells that lead to diseases such as cancer", says Professor Jussi Taipale at Karolinska Institutet's Department of Medical Biochemistry and Biophysics who led the research. The results pave the way for cracking the genetic code that controls the expression of genes, and will have broad implications for the understanding of development and disease. The availability of genomic information relevant to disease is expanding at an exponentially increasing rate. "This study identifies how the modification of the DNA structure affects the binding of transcription factors, and this increases our understanding of how genes are regulated in cells and further aids us in deciphering the grammar written into DNA", says Professor Taipale. The study was supported by the Academy of Finland Center of Excellence in Cancer Genetics and the ERA SynBio project MirrorBio, Karolinska Institutet's Center for Innovative Medicine, Knut and Alice Wallenberg Foundation, Göran Gustafsson Foundation, and the Swedish Research Council. Publication: Yimeng Yin, Ekaterina Morgunova, Arttu Jolma, Eevi Kaasinen, Biswajyoti Sahu, Syed Khund-Sayeed, Pratyush K. Das, Teemu Kivioja, Kashyap Dave, Fan Zhong, Kazuhiro R. Nitta, Minna Taipale, Alexander Popov, Paul A. Ginno, Silvia Domcke, Jian Yan, Dirk Schübeler, Charles Vinson, and Jussi Taipale. 'Impact of cytosine methylation on DNA binding specificities of human transcription factors'. Science, 5 May 2017.


PubMed | Karolinska Institutet, Center for Innovative Medicine, Northwestern University, Maastricht University and Copenhagen University
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

Hutchinson-Gilford progeria syndrome (HGPS) is a segmental progeroid syndrome with multiple features suggestive of premature accelerated aging. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. However, despite ubiquitous expression of lamin A in all differentiated cells, the HGPS mutation results in organ-specific defects. For example, bone and skin are strongly affected by HGPS, while the brain appears to be unaffected. There are no definite explanations as to the variable sensitivity to progeria disease among different organs. In addition, low levels of progerin have also been found in several tissues from normal individuals, but it is not clear if low levels of progerin contribute to the aging of the brain. In an attempt to clarify the origin of this phenomenon, we have developed an inducible transgenic mouse model with expression of the most common HGPS mutation in brain, skin, bone and heart to investigate how the mutation affects these organs. Ultrastructural analysis of neuronal nuclei after 70 weeks of expression of the LMNA c.1824C>T mutation showed severe distortion with multiple lobulations and irregular extensions. Despite severe distortions in the nuclei of hippocampal neurons of HGPS animals, there were only negligible changes in gene expression after 63 weeks of transgenic expression. Behavioral analysis and neurogenesis assays, following long-term expression of the HGPS mutation, did not reveal significant pathology. Our results suggest that certain tissues are protected from functional deleterious effects of progerin.


News Article | November 10, 2015
Site: www.scientificcomputing.com

A new study shows that the ‘grammar’ of the human genetic code is more complex than that of even the most intricately constructed spoken languages in the world. The findings, published in the journal Nature, explain why the human genome is so difficult to decipher — and contribute to the further understanding of how genetic differences affect the risk of developing diseases on an individual level. “The genome contains all the information needed to build and maintain an organism, but it also holds the details of an individual’s risk of developing common diseases such as diabetes, heart disease and cancer,” says study lead-author Arttu Jolma, doctoral student at Sweden’s Karolinska Institutet Department of Biosciences and Nutrition. “If we can improve our ability to read and understand the human genome, we will also be able to make better use of the rapidly accumulating genomic information on a large number of diseases for medical benefits.” The sequencing of the human genome in the year 2000 revealed how the three billion letters of A, C, G and T, which the human genome consists of, are ordered. However, knowing just the order of the letters is not sufficient for translating the genomic discoveries into medical benefits; one also needs to understand what the sequences of letters mean. In other words, it is necessary to identify the ‘words’ and the ‘grammar’ of the language of the genome. The cells in our body have almost identical genomes, but differ from each other because different genes are active (expressed) in different types of cells. Each gene has a regulatory region that contains the instructions controlling when and where the gene is expressed. This gene regulatory code is read by proteins called transcription factors that bind to specific ‘DNA words’ and either increase or decrease the expression of the associated gene. Under the supervision of Professor Jussi Taipale, researchers at Karolinska Institutet have previously identified most of the DNA words recognized by individual transcription factors. However, much like in a natural human language, the DNA words can be joined to form compound words that are read by multiple transcription factors. However, the mechanism by which such compound words are read has not previously been examined. Therefore, in their recent study in Nature, the Taipale team examines the binding preferences of pairs of transcription factors, and systematically maps the compound DNA words to which they bind. Their analysis reveals that the grammar of the genetic code is much more complex than that of even the most complex human languages. Instead of simply joining two words together by deleting a space, the individual words that are joined together in compound DNA words are altered, leading to a large number of completely new words. “Our study identified many such words, increasing the understanding of how genes are regulated both in normal development and cancer,” says Arttu Jolma. “The results pave the way for cracking the genetic code that controls the expression of genes.” This project was supported by the Finnish Academy CoE in Cancer Genetics, Center for Innovative Medicine, Knut and Alice Wallenberg Foundation, Göran Gustafsson Foundations, and the Swedish Research Council. Professor Taipale is also affiliated to the University of Helsinki, Finland. Citation: ‘DNA-dependent formation of transcription factor pairs alters their binding specificity,’ Jolma A, Yin Y, Nitta KR, Dave K, Popov A, Taipale M, Enge M, Kivioja T, Morgunova E and Taipale J., Nature , online November 9, 2015, doi: 10.1038/nature15518.


Baek J.-H.,Center for Innovative Medicine | Schmidt E.,Center for Innovative Medicine | Viceconte N.,Center for Innovative Medicine | Strandgren C.,Center for Innovative Medicine | And 10 more authors.
Human Molecular Genetics | Year: 2015

Hutchinson-Gilford progeria syndrome (HGPS) is a segmental progeroid syndrome with multiple features suggestive of premature accelerated aging. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. However, despite ubiquitous expression of lamin A in all differentiated cells, the HGPS mutation results in organ-specific defects. For example, bone and skin are strongly affected by HGPS, while the brain appears to be unaffected. There are no definite explanations as to the variable sensitivity to progeria disease among different organs. In addition, low levels of progerin have also been found in several tissues from normal individuals, but it is not clear if low levels of progerin contribute to the aging of the brain. In an attempt to clarify the origin of this phenomenon, we have developed an inducible transgenic mouse model with expression of the most common HGPS mutation in brain, skin, bone and heart to investigate how the mutation affects these organs. Ultrastructural analysis of neuronal nuclei after 70 weeks of expression of the LMNA c.1824C>T mutation showed severe distortion with multiple lobulations and irregular extensions. Despite severe distortions in the nuclei of hippocampal neurons of HGPS animals, there were only negligible changes in gene expression after 63 weeks of transgenic expression. Behavioral analysis and neurogenesis assays, following long-term expression of the HGPS mutation, did not reveal significant pathology. Our results suggest that certain tissues are protected from functional deleterious effects of progerin. © The Author 2014.


Balevicius Z.,Vilnius University | Balevicius Z.,Lithuanian Academy of Sciences | Drevinskas R.,Vilnius University | Dapkus M.,Vilnius University | And 3 more authors.
Thin Solid Films | Year: 2011

Total internal reflection ellipsometry (TIRE) technique was used to investigate the optical response of different hybrid multilayer systems. It was shown that the optical response was significantly changed by gold nanoparticles, which have been introduced for modification of functional properties of hybrid system. Nevertheless, the dispersion of optical parameters for gold nanoparticles was quite close in various hybrid systems in the case of adequate models used for interpretation of TIRE data. © 2010 Elsevier B.V. All rights reserved.


Characiejus D.,Vilnius University | Characiejus D.,Center for Innovative Medicine | Hodzic J.,VU University Amsterdam | Jacobs J.J.L.,VU University Amsterdam
EPMA Journal | Year: 2010

Present cancer treatment strategies are based on the assumption that a therapy may work ("response") or not work ("no-response"). However, the existing evidence suggests that current cancer treatment modalities may also have a cancer-promoting effect in part of the patients. In this paper, some relevant data are reviewed suggesting that surgery, irradiation, chemotherapy and immunotherapy can stimulate tumor growth / metastatic spread and decrease survival of patients in certain subgroups. Thus, results of cancer treatment may be improved by detection and use of biomarkers that correlate with positive or negative therapeutic effects. Small trials based on groups with differing biomarkers rather than large phase III trials may aid the development and efficacy testing of new anticancer drugs. Moreover, ignoring biomarkers that correlate with positive or negative therapeutic effect may not be compatible anymore with the ethical principle "First Do No Harm". © 2010 The Author(s).


Characiejus D.,Vilnius University | Characiejus D.,Center for Innovative Medicine | Jacobs J.J.L.,VU University Amsterdam | Pasukoniene V.,Vilnius University | And 4 more authors.
Anticancer Research | Year: 2011

This review focuses on the relationship between pre-treatment immune parameter values and outcome of immunotherapy of cancer patients. The evidence presented in this review suggests that there is a relationship between pretreatment immune parameter values and survival of cancer patients treated with immunotherapy. Tumour-infiltrating immune cells may have a predictive value for immunotherapy, but predictive power might be obtained from peripheral blood leukocytes. Use of peripheral blood may be preferable due to the convenience of collection and analysis compared to using tumour-infiltrating cells. In vivo numbers of cells of the immune system correlate better with clinical outcome than their functional activity ex vivo. This suggests that immunological antitumour mechanisms in vivo are not always related to generally accepted functional parameters of lymphocytes, such as cytotoxicity or cytokine production, ex vivo. The proliferative status of CD8+ T lymphocytes seems promising for prediction of response in cancer immunotherapy.


Jacobs J.J.L.,University Medical Center | Snackey C.,University Medical Center | Geldof A.A.,University Medical Center | Geldof A.A.,VU University Amsterdam | And 4 more authors.
Anticancer Research | Year: 2014

Prophylactic vaccination is arguably the most effective medical preventative method. After local inoculation, vaccines induce antigen-specific systemic immunity, protecting the whole body. Systemic antitumour immunity can cure advanced cancer, but will therapeutic vaccination suffice? A vaccine for castration-refractory prostate cancer (CRPC) was approved by regulatory authority, but its evidence is disputed. We critically reviewed the clinical efficacy of therapeutic cancer vaccines for prostate cancer, including the results of 31 clinical studies employing vaccines-only, and another 10 studies combining vaccines with immune co-stimulation. Vaccinations yielded immunological responses, but no study showed evidence for clinically relevant therapeutic improvement. Clinical failure of therapeutic vaccination is discussed in the light of immunological dogmas and mechanisms of antitumour therapies. We propose that cancer immunotherapy might be improved by immunological danger, i.e. disturbing tumour homeostasis by destroying the tumour tissue or inducing local inflammation. Such danger might override immunological tolerance, and thereby allow clinically relevant anticancer results.


PubMed | Center for Innovative Medicine and Vilnius University
Type: Journal Article | Journal: Anticancer research | Year: 2015

The aim of the present study was to analyze the survival, spatial distribution and proliferation of adoptively transferred lymphocytes in allogeneic tumor rejection.Transgenic -actin-luc mice that express luciferase were sensitized against SL2 tumors and were used as lymphocyte donors to study the anti-tumor effect in SL2 tumor-bearing lymphocyte-deficient RAG(-/-) mice. Whole-body bioluminescence images of recipient mice were obtained to track the adoptively transferred lymphocytes. Proliferation of lymphocytes was estimated by quantification of photon emission.T lymphocytes sensitized against allogeneic SL2 tumors cured the majority of SL2 tumor-bearing RAG(-/-) mice. Bioluminescence imaging showed that transferred T lymphocytes survived in the spleen and lymph nodes. Tumor rejection was associated with lymphocyte proliferation and migration to the tumor site.Sensitized T lymphocytes from transgenic -actin-luc mice reject allogeneic SL2 tumors in RAG(-/-) mice and can be tracked in vivo using bioluminescence imaging.


PubMed | Center for Innovative Medicine and Vilnius University
Type: Journal Article | Journal: Anticancer research | Year: 2016

To evaluate quantitative changes in B, NK and T lymphocyte subsets in peripheral blood of children with acute lymphoblastic leukemia (ALL) undergoing chemotherapy.Children with ALL were treated according to NOPHO ALL 2008 protocol. Levels of B lymphocytes (CD19Immunological analyses were performed in 25 children with ALL. Levels of B and NK lymphocytes decreased continuously during chemotherapy. In contrast, levels of most T lymphocyte subsets decreased only transiently and returned to pretreatment levels by days 78 to 85. The only T lymphocyte subset that did not return to the pretreatment level contained senescent CD3Immunomodulating action of chemotherapy in children with ALL results in reduction of proportion of senescent CD8

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