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tisdag 11 juli 2017

Käynnissä olevia tutkimustöitä Tampereella

University of Tampere: Taculty of Medicine and Life Sciences:

The Research Council for Health of the Academy of Finland granted five-year research fellowships to project director Ilkka Junttila and university researcher Keijo Viiri from the University of Tampere. Twelve fellowships were granted to eighty-five applicants, i.e. to fourteen percent of the applicants.

  • Ilkka Junttila’s study is investigating how cytokines, especially Interleukin(IL)-4, regulates allergic inflammation. Immune response protects people against invading pathogens such as viruses, bacteria, parasites and yeasts. Inappropriately activated immune response can result in an autoimmune reaction or an allergic reaction. Humoral mediators, cytokines, are critical regulators of various immune responses. By understanding how IL-4 and its cell surface receptors function, its therapeutic utilisation, for example in autoimmune diseases to redirect immune response to less inflammatory direction, may become possible. The study will be conducted in cooperation between the University of Tampere, Tampere University Hospital, Fimlab Ltd and National Institutes of Health (United States) and it is based on Junttila’s previous studies.

  • Keijo Viiri’s project will study the function of epigenetically dysregulated genes in coeliac disease. The main hallmark of the coeliac disease is the defectively differentiated intestinal epithelium, which leads to food malabsorption. The project previously discovered that an epigenetic gene-silencer called the polycomb controls the intestinal homeostasis between intestinal stem cells in crypts and mature epithelium in villi. In response to gluten ingestion, consequent aberrant polycomb activity was found to cause imbalance in intestinal homeostasis. The results are anticipated to reveal novel pathogenetic mechanisms and improve the diagnosis of the early coealiac disease.
Keijo Viiri’s Intestinal Signalling and Epigenetics group
http://www.uta.fi/tacc/research/signallingepigenetics/index.html

 Information in the genome is written in the bases of DNA and misspellings (mutations) in this code have sometimes profound effects leading to diseases. Yet, genome is not a static entity where information is only stored but it needs mechanisms to regulate the usage of this information i.e. gene activation and repression. Scientific advances in couple of last decades have taught us that there is a rather plastic interface between genome and environment. These epigenetic mechanisms include DNA methylation and plethora of different histone modifications which in turn regulate gene expression and a given gene expression state is inherited to the daughter cells. Perturbations in epigenetic mechanisms can also contribute to diseases such as cancer. One epigenetic regulator called ‘Polycomb’ has been shown to be overexpressed in endometrial-, breast-, colon-, lung-, and skin cancer. Cell type specific expression programs are orchestrated through regulated access to chromatin. Polycomb proteins regulate developmental gene expression. Polycombs are essential for embryonic stem cell self-renewal and pluripotency but they are also necessary for the maintenance of cell identity and cell differentiation throughout life. It has been shown that overexpressed polycomb keeps cells in more proliferative and lower differentiation state, which inevitably is one of the hallmarks of cancer.

Reminiscent to hyper-proliferative state in cancer the main manifestation of Celiac disease is also more proliferative and lower differentiation state, namely of the epithelium of the small intestine leading to food malabsorption. We’ve found that polycomb maintains the homeostasis between intestinal stem cells and mature epithelium. Moreover this homeostasis is broken when celiac patients are on gluten containing diet.

As celiac disease is an ailment with the strong autoimmune component in its pathogenesis we strive to understand how intestinal barrier (epithelium, immune cells and lamina propria cells) is dysregulated in the disease.  In our projects we use human and mouse primary cell cultures (intestinal organoids, primary myofibroblasts etc) and genome-wide techniques (such as ChIP-Seq) in endeavours to understand how signalling is reigned in intestinal barrier and how epigenetic mechanisms are running the errands of the signalling.

Figure 1. (A) Schematic representation of the role of Polycomb Repressive Complex 2 (PRC2) on enacting the Wnt/beta-catenin signaling and regulating the homeostasis of intestinal stem cell self-renewal and differentiation. At transit amplifying (TA) region PRC2 selectively set an epigenomic identity by labelling genes with repressive H3K27me3 mark and therefore enforce and maintain the dichotomy for crypt and villus identities. Scatter blot on the right demonstrates the genome-wide change in H3K27me3 occupancy during the differentiation of crypt/Intestinal stem cells to mature enterocytes. Blue dots represents all normalized differential H3K27me3 ChIP-Seq peaks near protein coding genes of the mouse genome (above genes silenced in crypts and below genes silenced in villi). Red coloured triangles denote the genes having significant gene expression difference measured by GRO-Seq and green arrows quantitatively illustrate the gene expression difference in enterocytes relative to crypts/ISCs (up=activation, down=repression). (B) PRC2 is out-of-bounds expressed and its enterocytic target genes are repressed in celiac patients on gluten-containing diet.

Figure 2. Growing ‘minigut’ organoids from intestinal stem cells harvested from mouse intestinal crypts. We use organoids as a model for intestinal differentiation. 24h after harvesting intestinal stem cells proliferate and visible spheres can be seen in three-dimensional matrigel cultures. Same spheroidal organoid after six days of culturing (Pictures in the same scale). With specific inhibitor and/or growth factor cocktails organoids can be differentiated virtually to any intestinal epithelial cell type ex vivo.

Group members

Keijo Viiri, Group leader
PhD
Mikko Oittinen (MSc, PhD student)
Joel George (MSc, PhD student
Jorma Kulmala (Laboratory technician, part-time)

Selected Publications

    Oittinen M, Popp A, Kurppa K, Lindfors K, Mäki M, Kaikkonen MU & Viiri K. ”PRC2 enacts Wnt signaling in intestinal homeostasis and contributes to the instigation of stemness in disease entailing epithelial hyperplasia or neoplasia” Stem Cells 2017 Feb; 35(2):445-457

    Teppo S, Laukkanen S, Liuksiala T, Nordlund J, Oittinen M, Teittinen K, Grönroos T, Syvänen AC, Nykter M, Viiri K, Heinäniemi M, Lohi O. Genome-wide repression of eRNA and target gene loci by the TEL-AML1 fusion in acute leukemia” Genome Research 2016 Nov;26(11):1468-1477

    Beltran M, Yates CM, Skalska L, Dawson M, Reis FP, Viiri K, Fisher CL, Sibley CR, Foster BM, Bartke T, Ule J & Jenner RG. “The interaction of PRC2 with RNA or chromatins is mutually antagonistic” Genome Research 2016 Jul; 26(7):896-907.

    Mäntylä E, Salokas K, Oittinen M, Aho V, Mäntysaari P, Palmujoki L, Kalliolinna O, Ihalainen TO, Niskanen EA, Timonen J, Viiri K, Vihinen-Ranta M. ”Promoter-Targeted histone acetylation of chromatinized parvoviral genome is essential for the progress of infection” Journal of Virology 2016 Mar 28;90(8):4059-66.

    Hervonen K, Salmi TT, Ilus T, Paasikivi K, Vornanen M, Laurila K, Lindfors K, Viiri K, Saavalainen P, Collin P, Kaukinen K, Reunala T. ”Dermatitis herpetiformis refractory to gluten-free dietary treatment.” ActaDermato-Venereologica. 2016 Jan; 96(1):82-6.

    Vlachogiannis G, Niederhuth CE, Tuna S, Stathopoulou A, Viiri K, de Rooij DG, Jenner RG, Schmitz RJ, Ooi SK. “The Dnmt3L ADD domain Controls cytosine methylation establishment during spermatogenesis.” Cell Reports. 2015 Feb 12.

    Viiri K, Mäki M, Lohi O. “Phosphoinositides as regulators of protein-chromatin interactions.” Science Signaling. 2012 May 1; 5(222):pe19.

    Kanhere AS, Viiri K, Araújo CC, Rasaiyaah J, Bouwman RD, Whyte W, Pereira CF, Brookes E, Walker K, Bell GW, Pombo A, Fisher AG, Young RA , Jenner RG “Short RNAs are transcribed from repressed Polycomb target genes and interact with Polycomb Repressive Complex-2”. Molecular Cell 2010 Jun 11;38(5):675-88


Funding

Academy of Finland
TEKES – the Finnish Funding Agency for Technology and Innovation
Sigrid Jusélius Foundation
IASR – Institute for Advanced Social Research
Sohlberg Foundation

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