Open Phd Positions at the Institute of Molecular Genetics of the ASCR, V. V. I

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Open Phd Positions at the Institute of Molecular Genetics of the ASCR, V. V. I

Open PhD positions at the Institute of Molecular Genetics of the ASCR, v. v. i.

http://www.img.cas.cz/studium/phd-program/

Laboratory of Haematooncology http://www.img.cas.cz/research/meritxell-alberich-jorda

Research topics: Mechanisms of leukemogenesis

Acute myeloid leukaemia (AML) is a malignant haematopoietic disease that represents over 90% of acute leukaemias in adults. Minute changes in expression of critical transcription factors have been shown to deregulate haematopoiesis and aberrations in myeloid transcription factors have been observed in AML patients. Our research team is particularly interested in the CCAAT/enhancer binding protein (C/EBP) transcription factor family, which regulates the commitment of haematopoietic stem cells towards the myeloid lineage. Specifically, we investigate the functions of C/EBPγ and C/EBPα transcription factors and their target genes in normal haematopoiesis and malignant transformation in AML. Also, we aim to identify small-molecules able to reactivate targets of the C/EBPα, ultimately resulting in therapeutic restoration of granulocytic differentiation in AML.

Candidate’s profile (requirements):

Candidate should hold a M.Sc. (Mgr.) degree, should be experienced in molecular and cell biology techniques, and willing to work on mouse models. Candidate should be enthusiastic, motivated and have good English level.

PhD Project:

Biology of normal and leukemic blood cells. We offer the possibility to perform an exciting Ph.D program in a friendly environment, with broad training in vitro cultures/molecular biology and in vivo murine models. The project may lead to international collaborations and assistance to international conferences.

Supervisor: Meritxell Alberich-Jorda ([email protected]) Laboratory of Genome Integrity www.img.cas.cz/research-groups/jiri-bartek

Research topics: Maintenance of genome stability, oncogene-induced replication stress, RecQ DNA helicases, R-loops, replication-transcription collisions

DNA damage is a frequent event in the life of a cell. Failure to repair DNA damage can lead to cell death, while inaccurate DNA repair can give rise to genomic instability, which promotes the onset of cancer in mammals. Research in our laboratory focuses on understanding various DNA repair mechanisms operative in mammalian cells. Our main aim is to define the exact DNA transactions mediated by RecQ DNA helicases, key players in the maintenance of genomic stability. Recently, we obtained funding from the Czech Science Foundation to study molecular mechanisms underlying the formation and resolution of RNA:DNA hybrids (R-loops), highly genotoxic structures that can arise as a consequence of collisions between replication and transcription machineries. This is an extremely important, but not well understood, aspect of the maintenance of genome stability that attracts more and more scientists worldwide.

Candidate’s profile (requirements):

M.Sc. (Mgr.) degree or equivalent in biochemistry or molecular/cellular biology, good English, independent thinking, strong interest in basic research and experimental work

PhD project:

The PhD project will be focused on identification of proteins associated with R-loops under conditions of chemically- and oncogene-induced replication stress and studying their role in maintenance of genome stability. The project offers training in a broad range of molecular, cell biological and biochemical techniques. The student will also undergo short-term trainings at the Institute of Molecular Cancer Research of the University of Zurich where he/she will be exposed to front-line research in the field of DNA repair and cancer.

Supervisor: Jana Dobrovolná ([email protected])

Co-supervisor: Pavel Janščák ([email protected])

Laboratory of Cell Differentiation www.img.cas.cz/research-groups/petr-bartunek

Research topics: Chemical genetics, haematopoietic and neural cell differentiation, signalling pathways, nuclear receptors The main interest of the laboratory lies in the molecular mechanism of cell fate determination. In the lab we have established in vitro systems to study the self-renewal and differentiation of haematopoietic, neural and mesenchymal stem cells. We use growth factors and small molecules as tools to manipulate these systems. More recently, we have initiated more systematic search for such tools using chemical biology/genetics approaches. Candidate’s profile (requirements):

MSc or equivalent in molecular and developmental biology.

PhD project:

Title: Mouse transgenic models for sterol-sensing domain containing proteins

The project will focus on generation of knock-out models (CRISPR/Cas9 and Cre/lox) for functional analysis of recently discovered gene Disp3 during development and characterization of already established neural-specific transgenic lines. Succesful candidate will employ broad range of advanced molecular and cell biology methods and imaging techniques. Supervisor: Petr Bartůněk ([email protected])

Laboratory of Cell and Developmental Biology www.img.cas.cz/research-groups/vladimir-korinek

Research topics: Colorectal cancer, Wnt signalling, TCF/LEF transcription factors, Hypermethylated in Cancer 1, HIC1

The majority of tissues in the adult organism contain a population of tissue-specific stem cells. These multipotent cells are involved in homeostatic self-renewal and tissue repair processes. The biology of the stem cells is driven by a limited set of signalling cascades. The deregulation of these cascades can ultimately lead to the cellular transformation and formation of tumours. This clearly indicates the connection between the stem cell physiology and cancer. The scientific goal of the laboratory is to elucidate molecular mechanisms influencing behaviour of normal and diseased intestinal epithelial cells. Since the fate of these cells is determined by the so-called Wnt signalling pathway, our main focus is to find genes regulated by the Wnt pathway and/or encoding proteins directly involved in the signalling process.

Candidate’s profile (requirements): Applicants should hold a diploma/masters’ degree in biology/life sciences with an excellent background in cell biology and have strong laboratory, quantitative and communication skills. PhD project:

Polycythemia vera (PV) is a hematological neoplasm with prolong survival but approximately 15% of the cases progress to myelofibrosis and acute myeloid lekuemia. The full mutation landscape and whether and how these alterations contribute to disease initiation and clonal evolution or myelofibrotic transformation are not fully deciphered. Using patient specific iPSCs we would like to address the relevant molecular changes which lead to the pathogenesis and progression of PV.

Supervisor: Lucie Láníková ([email protected])

Laboratory of Transcriptional Regulation www.img.cas.cz/research-groups/zbynek-kozmik http://kozmik.img.cas.cz/

Research topics: Eye development and evolution, Pax genes, Wnt/β-catenin signalling

We are interested in the genetic basis of mammalian eye development. Our focus is on the role of transcription factors and signalling cascades, especially on the role of Pax6 gene, Wnt/β-catenin signalling pathway and their genetic interaction. A combination of gain-of- function (transgenic) and loss-of-function (conditional knock-outs) approaches is used. Our second main interest is eye evolution. Early morphological studies have suggested that eye has evolved multiple times during the course of evolution. In contrast, more recent genetic data indicate a conserved role of Pax6 and some other transcription factors in eye formation in a wide range of animals. Several model systems including amphioxus, scallop, medaka and jellyfish are used in the laboratory to study various aspects of eye evolution.

Candidate’s profile (requirements):

M.Sc. or equivalent in molecular, cell or developmental biology, or in biochemistry.

PhD project 1:

One or two PhD positions are available in the area of evolutionary-developmental biology (evo-devo). Projects will deal with eye evolution and/or evolution of cell types. Evolution of genes and gene regulatory networks will be studied using selected animal models available in the laboratory (zebrafish, amphioxus, annelid worm, cnidaria). The methods used will include bioinformatics, gene isolation, gene expression studies by in situ hybridization, transgenesis and gene knockouts by TALENs and Crispr/Cas9 systems.

Supervisor: Zbyněk Kozmik ([email protected])

PhD Project 2:

Two PhD positions are available in the area of developmental biology. Projects will focus on the role of transcription factors in vertebrate eye development using laboratory mouse as a model system. The methods used will include gene knockouts using Cre/loxP TALENs and Crispr/Cas9 technologies, gene expression studies of mutant mice by in situ hybridization, immunohistochemistry, RNA-seq and/or microarrays. In addition, gene regulatory networks will be interrogated by using ChIP-seq and reporter gene assays in cell lines and transgenic animals.

Supervisor: Zbyněk Kozmik ([email protected])

Laboratory of Cancer Cell Biology www.img.cas.cz/research-groups/libor-macurek

Research topics: Cell cycle, checkpoint, protein phosphorylation, oncogenic transformation In our recently established laboratory we employ cell biology, molecular biology and biochemical approaches to identify molecular mechanisms that control cellular responses to DNA damage. In particular we focus on protein phosphatase PPM1D/Wip1 that plays an essential role in switching off the DNA damage response pathway, termination of the checkpoint and control of checkpoint recovery. PPM1D/Wip1 is an important negative regulator of the tumor suppressor p53. Recent data from transgenic mice and from human tumors implicate PPM1D/Wip1 as oncogene. Our work aims to decipher molecular mechanisms regulating function of PPM1D/Wip1 in human cells and in mouse models. In addition, we use chemical genetics to evaluate PPM1D/Wip1 as a potential pharmacological target.

Candidate’s profile (requirements): Eligible candidates should have M.Sc. degree or equivalent in cell/molecular biology or biochemistry and show a deep interest in experimental work. Highly motivated applicants are encouraged to contact directly Libor Macurek at [email protected]. PhD Project:

Title: Role of PPM1D/Wip1 mutations in cancer predisposition Genome integrity of eukaryotic cells is protected by a DNA damage response pathway (DDR) that coordinates the cell cycle progression with ongoing DNA repair. In the Cancer Cell Biology lab we use cell/molecular biology and biochemical techniques to study molecular mechanisms underlying these events. In particular we focus on Wip1 phosphatase that directly regulates tumour suppressor protein p53 and several other target proteins and plays role in termination of DDR after DNA repair. Recently we have identified novel clinically relevant mutations in the PPM1D gene that result in production of a truncated, abnormally stable form of Wip1. This PhD project will focus on investigation of molecular mechanisms that control stability and enzymatic activity of Wip1 in cells.

Supervisor: Libor Macůrek ([email protected])

Laboratory of RNA Biology www.img.cas.cz/research-groups/david-stanek

Research topics: RNA splicing, spliceosome formation, alternative splicing, retinitis pigmentosa, nuclear structure

Our long-term interest is to determine how cells decode information stored in the genome. Information in human DNA is fragmented and we study processes and complexes that splice these fragments together. We focus on molecules called RNAs that serve as information couriers between DNA and proteins.

Candidate’s profile (requirements):

M.Sc. in molecular, cellular or developmental biology, biochemistry or biophysics

PhD project:

Research of mutation in splicing proteins, which causes hereditary degeneration of eye retina. The main goal is to determine, how mutation affect specifically photoreceptors. This include expression of mutant proteins in cell culture as well as preparation of animal models, namely zebrafish, and eye organoids, that express mutated proteins.

Supervisor: David Staněk ([email protected])

Laboratory of Epigenetic Regulation www.img.cas.cz/research-groups/petr-svoboda PhD position 1 – bioinformatics

Project title: Small RNAs and transcriptomes in mammalian oocytes and early embryos Candidate profile: M.Sc. or equivalent in molecular biology or informatics (mathematics, statistics). The minimal requirement is some bioinformatics experience (genomics, gene expression analysis, modelling …), solid background in mathematics/statistics and computers, and a strong motivation to learn. An ideal candidate should know at least one programming language (python/perl/C/C++), one mathematical/statistical programming language (matlab/R), UNIX OS, and have some experience with designing, analyzing and implementing algorithms. Experience with analyzing data from microarray profiling or high-throughput sequencing is an advantage. Project description: The project focuses on bioinformatics analysis of various aspects of gene expression during oocyte-to-zygote transition, including analysis of retrotransposon expression, long non- coding RNAs, small RNAs (miRNA, piRNA, siRNA), maternal mRNA degradation and zygotic genome activation. The candidate will be involved in comparative genomics of different mammalian models and will use bioinformatics data to test conservation and divergence of mechanisms controlling gene expression in mammalian oocytes and early embryos Supervisor: Petr Svoboda ([email protected])

PhD position 2 – developmental/molecular biology Project title: Functions of small RNAs in the female germline in mammals Candidate profile: M.Sc. or equivalent in molecular, cell or developmental biology. The minimal requirement is knowledge of basic molecular biology (at least molecular cloning, nucleic acid isolation & RT- PCR), a solid knowledge base in biology, and curiosity. Previous experience with mice, cell culture (especially oocytes and early embryos), confocal microscopy, genomics or high throughput expression analysis is a major advantage. Project description: The project will focus on functional analysis of small RNA pathways in the mammalian female germline. The candidate will explore function of small RNAs in oocytes of mice, hamsters and cow, analyze phenotypes of genetically modified mouse models, and will participate in development of a genetically modified hamster model. Supervisor: Petr Svoboda ([email protected]) Laboratory of Mouse Molecular Genetics www.img.cas.cz/research-groups/jiri-forejt

Research Topics: Genetic control of meiotic recombination and hybrid sterility, epigenetic inheritance, genetics and the origin of species

Meiosis is a unique type of cell division producing haploid gametes. Meiotic recombination assures proper segregation of chromosomes into gametes and genetic variation among offspring. Meiosis also functions as a barrier to filter out deleterious genic and chromosomal mutations and to prevent gene flow between species. Recently, we identified the first hybrid sterility gene in vertebrates, Prdm9, and the interacting Hstx2 locus on chromosome X. The role of these two genetic factors in meiotic recombination and in reproductive isolation between two closely related mouse subspecies, as well as the transmission of epigenetic marks through meiosis are the cutting-edge topics of the genetics of speciation currently studied in the lab.

Candidate's profile:

M.Sc. (Mgr.) degree or equivalent in molecular genetics with strong interest in basic research

PhD project:

The role of meiotic recombination and epigenetic inheritance in reproductive isolation between related species

Supervisor: Petr Jansa ([email protected])

Co-supervisor: Jiří Forejt ([email protected])

Laboratory of Germ Cell Development http://www.phenogenomics.cz

Research Topic:

The current fertility studies in model mammals move from the effects of single gene to genetic interactions important for human reproductive medicine that occur during spermatogenesis and oogenesis. The Prdm9 gene (also called Meisetz) is necessary for both male and female meiosis and fertility in the laboratory mouse. The biochemical function of the PRDM9 protein is to methylate histones. The mouse, bovine, and human PRDM9 proteins specify the sites of meiotic recombination. However, PRDM9 is dispensable for fertility in the dog. PRDM9 polymorphisms were revealed in sterile human patients and PRDM9 variation contributes to instability of the human genome. We have identified Prdm9 as the first vertebrate hybrid sterility gene. Different Prdm9 mutations display different stages and degrees of spermatogenetic arrest on various backgrounds, indicating that the resulting phenotype is dependent on genetic interactions of Prdm9.

The project aims are: analyses of genes regulating germ cell development in mouse and rat testes and ovaries, interspecific differences important for translation studies; analyses of interactions and incompatibilities of genes expressed in testes and ovaries; analyses of models of germ cell development defects that are affected by Prdm9, including complete meiotic arrest (azoospermia), limited fertility (reduced sperm count - oligospermia), sperm head malformations (teratozoospermia), and reproductive age defects (time-dependent arrest of germ cell development).

Candidate's profile:

M.Sc. or equivalent in molecular genetics (molecular biology), active English

PhD project:

Cloning of genes affecting fertility, specifying the role of Prdm9 and other meiotic genes in rodent gametogenesis. Among the techniques applied will be: fertility phenotyping including fluorescent microscopy, genotyping, sequencing, gene expression analyses.

Supervisor: Zdeněk Trachtulec ([email protected])

Laboratory of Biology of Cytoskeleton www.img.cas.cz/research-groups/pavel-draber

Candidate profile:

M.Sc. or equivalent in molecular biology, developmental biology, biochemistry, immunology. Ing. or equivalent in molecular biology, biochemistry, microbiology

PhD Project:

Regulatory mechanism or microtubule organization in activated mast cells. Role of GTPase exchange factors (GEFs) in modulation of microtubule nucleation. In the project will be applied methods of molecular cell biology, state of the art microscopic techniques, live cell imaging and gene editing.

Supervisor: Pavel Dráber ( [email protected] ), http://www.img.cas.cz/dbc/ Laboratory of Integrative Biology http://www.img.cas.cz/research/martin-gregor/

Candidate profile:

We are seeking outstanding self-motivated candidates with master's degree in molecular biology, physiology, general biology, biochemistry or related fields. We are offering research at a state-of-the-art equipped institute with experienced colleagues, international working environment and international collaborations.

Applications are invited for Ph.D. student positions in the Department of Integrative Biology, at the Institute of Molecular Genetics of the ASCR, v. v. i. (IMG, Prague, Czech Republic). The positions (up to five years) are fully funded by several grants.

The successful candidates will learn and utilize advanced cell-biology, molecular-biology and imaging techniques, while developing and analyzing various mouse models. In particular, the research will focus on one of the following topics:

 The impact of liver-specific deficiency of plectin on tensional homeostasis and pathology We have recently shown that plectin controls keratin cytoarchitecture and cellular stress response. Based on our preliminary results we hypothesize that plectin confers features of keratin networks essential for their hepatoprotective function. Major focus will be on characterizing and comparing pathogenesis of acute, chronic and biliary fibrosis using our newly generated liver-specific plectin knock-out mouse model.

 The role of plectin in cell motility and invasion of hepatocellular carcinoma Hepatocellular carcinoma HUH7 cells devoid of individual plectin isoforms will be characterized in 2D and 3D migration assays, colony and sphere formation assays and using traction microscopy and microrheology techniques. In collaboration, isoform-dependent effects of plectin on tumorigenicity will be assessed in orthotopic murine model and human HCC samples will be screened for plectin isoform expression patterns.

 The role of junctional and desmosomal constituents on architecture and barrier function of the intestinal epithelia Dysfunction of intestinal epithelial barrier is a hallmark of many pathological processes. Recently, tight junctions (TJ) and desmosomes (DS) were proposed to play crucial role in disease pathogenesis. The major objective of this project is to study the role of model constituents of TJ (claudin 8 and 13) and DS (plectin) in protection of intestinal simple epithelia from inflammation and tumorigenesis.  Defining “matrisome” of healthy and fibrotic liver Proteomics-based approach (mass spectrometry and bioinformatic analysis) will be employed to define ECM and cytoskeletal composition of normal and fibrotic liver tissues in murine models of liver fibrosis.

Supervisor: Martin Gregor ([email protected] ) For background information see: https://www.researchgate.net/profile/Martin_Gregor/?ev=prf_highl

Laboratory of Biology of the Cell Nucleus www.img.cas.cz/research-groups/pavel-hozak

PhD position 1

Research topics: : Phosphoinositides compartments in the cell nucleus – their structure and functions

Phosphoinositides are phosphorylated species of phosphatidylinositol. They are present at all membranous structures within a cell (plasma membrane, ER, GA, endosomes and various vesicles) where they direct membrane trafficking and serve as signalling molecules. Surprisingly, phosphoinositides localize also to the cell nucleus, which is internally absent of membrane. We have previously demonstrated that phosphatidyl inositol-4,5-bisphosphate (PIP2) is present in the nucleolus as well as carbon-rich patches which we termed the lipid islets. We have shown that nucleolar PIP2 stimulates activity of RNA polymerase I and other transcription factors such as UBF and fibrillarin and thus modulates transcription of rDNA genes. In the nucleoplasm, lipid islets associate with RNA polymerase II and their absence negatively affects transcription of protein-coding genes. The exact mechanism, however, remains largely unknown. This project focuses on finding (i) the detailed composition of lipid islets as well as (ii) defining a cross-talk between various phosphoinositides within the nucleus, (iii) defining direct protein interacting partners of phosphoinositides, and (iv) elucidating the mechanism by which the phosphoinositides modify nuclear processes, e. g. RNA polymerase II transcription.

PhD project:

The PhD project will implement molecular biology and biochemistry methods as well as the state-of-the-art imaging techniques including fluorescence, confocal and super-resolution (SIM, STED) microscopy. The project is supported by recently awarded funding from the Grant Agency of the Czech Republic.

Candidate’s profile (requirements):

M.Sc. (Mgr.) degree or equivalent in molecular/cellular biology, good English, independent thinking, strong interest in basic research and experimental work

Supervisor: Pavel Hozák ([email protected])

PhD position 2

Research topics: Nuclear periphery and its role in chromatin organisation

A nuclear periphery involves a nuclear envelope with a lamina tightly attached to the inner nuclear membrane and nuclear pore complexes facilitating nucleocytoplasmic transport. The nuclear periphery plays a crucial role in chromatin organisation, regulation of gene transcription, gene silencing or in mediating the communication between the nucleus and the cytoplasm. The importance of the nuclear periphery is also demonstrated by number of diseases (called envelopathies) resulting from a mutation in genes encoding for one of the peripheral protein such as lamin or emerin. The structure of the nuclear periphery as well as the role of proteins associated with the periphery in the above mentioned processes is fragmentary. This project focuses on those topics and aims to further uncover the significance of nuclear periphery proteins as well as the role of nucleocytoplasmic transport for nuclear organisation. The project is supported by recently awarded funding from the Grant Agency of the Czech Republic.

PhD project:

The PhD project will implement the state-of-the-art imaging techniques including super- resolution (SIM, STED) and electron microscopy (TEM, SEM) as well as molecular biology and biochemistry methods for in-depth studies of the organisation of the nuclear periphery and the role of periphery associated proteins in chromatin organisation. The student will also undergo a short-term stay at the University of Durham, United Kingdom, in the laboratory of Dr. Martin Goldberg.

Candidate’s profile (requirements):

M.Sc. (Mgr.) degree or equivalent in molecular/cellular biology, good English, independent thinking, strong interest in basic research and experimental work Supervisors: Jindřiška Fišerová ([email protected]) and Pavel Hozák ([email protected])

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