2012-14   2009-11   2006-08   2003-05   2000-02   1997-99   1994-96

Максим Франк-Каменецкий

Boston University, США

Новое в биофизике молекулы ДНК

Две традиционных темы биофизики молекулы ДНК, флуктуационные рескрытия двойной спирали и «изломы» двойной спирали при больших изгибных деформациях, неожиданно оказались тесно связанными друг с другом. Совершенно неожиданным оказалось открытие еще одного, наряду с флуктуационными раскрытиями, типа флуктуационной подвижности двойной спирали, получившего название «хугстиновских дыханий». Это заставило пересмотреть старые данные о реакции ДНК с формальдегидом. В свою очередь, реакция ДНК с формальдегидом приобрела чрезвычайную актуальность в связи с тем, что было показано, что формальдегид накапливается в ядре клетки как побочный продукт деметилирования гистонов хроматина, и что это накопление может приводить к весьма плачевным последствиям.

Павел Новичков

Lawrence Berkeley National Laboratory, США

Mo/W homeostasis in sulfate reducing bacteria is controlled by transcription factors evolved from recombination proteins XerC/XerD and Xis

Molybdenum and tungsten are both essential and toxic metals for sulfate reducing bacteria, and thus their homeostasis needs to be tightly regulated.

We combined comparative genomics and experimental approaches to study the transcriptional regulation of Mo/W homeostasis in model sulfate reducing bacterium Desulfovibrio vulgaris Hildenborough and sixteen other Desulfovibio spp. Here we report two novel families of transcriptional regulators named TunR and TaoR, predicted to control genes involved in Mo/W transport, as well as Mo/W containing enzymes. The striking feature of these novel families is that they appear to have evolved from XerC/XerD and Xis recombination proteins by fusion with domains known to be implicated in molybdenum binding, TOBE domain (PF03459) and periplasmic molybdate-binding domain (COG1910).

We provide multiple lines of genomic-based evidence that the role of the DNA-binding domain of the TunR family regulators is fulfilled by the evolved site-specific tyrosine recombinase XerC/XerD, which accumulated mutations in the active-site residues, and ultimately lost its catalytic function. The unique feature of the TunR family is that the members of this family were found exclusively in sulfate-reducing delta-proteobacteria. The TunR regulon, reconstructed by comparative genomics, suggests that regulators from this family control genes encoding molybdate/tungstate ABC transporters ModABC and TSUP family transporters. The DNA-binding domain of the TaoR regulators belongs to Xis family, the typical representative of which is excisionase encoded by Xis gene in bacteriophage lambda. The predicted TaoR targets are a formate dehydrogenase, a tungstate-specific ABC-type transporter and an aldehyde ferredoxin oxydoreductase.

The examination of expression of the predicted target genes in regulatory mutants demonstrated that both TunR and TaoR are tungstate-responsive transcriptional regulators in D. vulgaris Hildenborough. TaoR was also found to have a strong co-fitness with genes encoding members of Mo/W cofactor biosynthesis pathway in Desulfovibrio alaskensis G20. Finally, computationally predicted transcriptional factor binding sites have been tested and validated by electrophoretic mobility shift assays.

Денис Ларкин

Королевский Ветеринарный Колледж, Университет Лондона, Великобритания

Хромосомная эволюция млекопитающих и птиц: сходство и различия

Недавний прогресс в расшифровке геномов животных обеспечил нас базовым материалом для их детального сравнения. Это сравнение может пролить свет на закономерности эволюции геномов, включая реорганизацию хромосом в ходе эволюции. Наиболее важными вопросами являются вопросы о случайности или предопределенности позиций хромосомных перестроек, особенности организации хромосом в районах эволюционных разрывов, связи эволюционных хромосомных разрывов и фенотипов, а так же степени реорганизации предкового генома у представителей разных классов животных. В моем докладе будет представлен обзор наших работ в области геномики эволюционных хромосомных разрывов млекопитающих и птиц, проливающих свет на эти и некоторые другие аспекты эволюции хромосом.

Анна Герасимова

La Jolla Institute for Allergy and Immunology, США

Integrated study of genetic variations and epigenetic data

Using ENCODE data; we demonstrate that non-coding disease-associated SNPs are enriched in enhancers of cell types that are driving disease pathogenesis. (Gerasimova et al, 2013, PMID: 23382893).

Specifically, we show that asthma-associated SNPs are enriched in regulatory regions active in CD4+ T cells.

We continue to build on the result above by analyzing our in-house data (Seumois, et al, 2014, PMID: 24997565). By doing that, we have detected that the enhancers gaining the (H3K4me2) mark during Th2 development show the highest enrichment for asthma-associated SNPs – which supports a pathogenic role for Th2 cells in asthma.

Дмитрий Осмаков

iBinom

Машинное обучение в задаче аннотации вариантов в геноме человека

- Существующие базы данных и инструменты аннотации (Annovar, SNPeff, Polyphen, SIFT).
- Составление обучающей выборки для алгоритмов машинного обучения и анализ характеристики этой выборки.
- Выбор алгоритма машинного обучения и анализ патогенных вариантов с точки зрения алгоритма.
- Дальнейшие возможности по улучшению биологической интерпретации.

Василий Раменский

Центр нейрогенетики ун-та Калифорнии в Лос-Анджелесе, США

Секвенирование как инструмент исследования сложных фенотипов: от генов к полным геномам

Будет рассказано о поиске генетических факторов, влияющих на сложные фенотипы, на примере количественных метаболических признаков, синдрома Туретта и биполярного аффективного расстройства.

Инна Дубчак

Lawrence Berkeley National Laboratory

Visualization of genomic data: results, challenges, and open questions

As our ability to generate huge amounts of sequencing data continues to increase, data analysis is becoming the rate-limiting step in genomics studies. Visualization tools facilitate analysis tasks by enabling researchers to explore, interpret and manipulate their data. There are a number of graphical methods designed for the analysis of de novo sequencing assemblies and read alignments, genome browsing, comparative genomics, etc. All available visualization tools have their strengths and limitations. We will highlight new challenges in visualization that are not only a consequence of the sheer volume and complexity of genomic data, but also its increasing utility outside genomics research. Traditional genome visualization approaches do not meet the needs of emerging fields such as medical genomics and metagenomics, and new paradigms are needed. Clinicians require efficient presentation of critical information in order to form a diagnosis, and biobanks and population studies produce detailed phenotype descriptions too complex to represent as a heat map or other form of tabular visualization. These data can reveal the effect of spatial and environmental factors on population and ecosystem structure, but interactive, extensible, easy to use tools must be provided to enable their analysis and exploration.

Ольга Калинина

Max-Planck-Institut fur Informatik (Saarbrucken, Германия)

Horizontal gene transfer in viruses

The origin and evolution of viruses is a subject of ongoing debate: viruses do not belong on the common tree of life that unites all cellular organisms on Earth. It also is unknown whether viruses have one common origin, or multiple independent sources, and to which extent they share a common evolutionary history. We have looked for events of horizontal gene transfer in viruses in two ways. First, we have extracted all close homologs between viruses that use different type of amino acid, and hence are extremely unlikely to descend from a common ancestor. We have been able to identify over a hundred of genes, of which most encode for probably functional proteins that are engages in the nucleic acid processing and replication. We have not been able to prove gene transfer between viruses, but in several cases we can observe gene transfer from the host. In the second part, we have developed a machine learning technique to identify genes that are atypical for a given virus family, and hence have been horizontally transferred from elsewhere. The method does not depend in sequence comparison, and so can identify transfer event from organisms that have not been sequenced yet, and its computation time depend only on the size of the viral family. We have been able to rediscover known and predict many new gene transfer event.
Докладчик

Всеволод Макеев, Иван Кулаковский, Илья Воронцов и консорциум FANTOM5

Институт общей генетики им. Н.И.Вавилова РАН

Обзор предварительных результатов 5й стадии проекта FANTOM по функциональной аннотации генома млекопитающих

Проект FANTOM (Functional ANnoTation Of Mammals) осуществляется международным консорциумом, организованным Yoshihide Hayashizaki (RIKEN, Yokohama, Japan) и его коллегами в 2000 году для изучения транскриптов и транскрипционных регуляторных сетей у млекопитающих. На пятой стадии проекта были получены промоторы, экспрессирующиеся более, чем в 200 типах клеток у человека и мыши (всего около 1400 образцов). Для этого использовалась технология CAGE Cap Analysis of Gene Expression) дополненная секвенированием одиночных молекул Helicos. Проект дает уникальную информацию об архитектуре промоторов млекопитающих, тканеспецифичности и уровнях экспрессии, а также о ключевых регуляторах состояния клетки и функциях основных кодирующих и некодирующих транскриптов. В презентации будут объяснены основные типы данных, которые станут доступны в течении ближайших нескольких месяцев, а работа по определению роли мотивов в ДНК, ответственных за специфическое связывание факторов регуляции транскрипции и формировании специфического профиля экспрессии промоторов.

Philipp Khaitovich

Max Planck – CAS Partner Institute for Computational Biology (Shanghai, China)

Transcriptome evolution of cortical layers in primate brain

Changes in brain organization are likely to be central to evolution of human cognition. Most of the previous studies of gene expression signatures specific to the human brain focused on human-specific transcriptome features identified in homogenized brain tissue samples. Human neocortex, however, features complex laminar architecture with district histology and functionality in each of the cortical layers. So far, however, human-specific features of the cortical organization remain unknown. Here, we present a study of polyA-plus transcriptomes measured in individual cortical layers of prefrontal cortex in three primate species: humans, chimpanzees and rhesus macaques. Over half of genes expressed in brain showed significant expression differences across layers reflecting differences in their organization and functionality. Genes with lineage-specific expression profile changes were identified on all three evolutionary linages and characterized with respect to their potential contribution to brain functions.

Максим Имакаев

Massachusetts Institute of Technology

Comparison of chromosomal organization across species

Chromosomes are among the most iconic structures in the cell, yet the details of chromosomal organization remain disputed. This talk discusses how Hi-C, a genome-wide method for chromosome conformation capture, can be used to characterize the three-dimensional folding of chromosomes from various organisms, focusing on the bacterium Caulobacter crescentus and budding (S.cerevisiae) and fission (S.pombe) yeast. First, I will discuss the organism-specific features of the Hi-C contact maps. I will then show how polymer simulations can be used to build first-principles models of chromosomal folding, and how these models can be validated against the Hi-C and microscopy data. Unlike genomic tracks, which are a one-dimensional readout, Hi-C data is intrinsically two-dimensional (a genome-by-genome contact matrix), and requires special approaches to analyze the data. Moreover, Hi-C does not provide direct information about spatial organization of chromosomes. Therefore, spatial organization must be inferred using indirect methods. To this end, we took an "ab initio" approach and built high-resolution polymer models based on existing knowledge and hypothesis about chromosomal organization. We then compared these models to Hi-C and microscopy data. We performed Hi-C in C.crescentus under a range of conditions and for several points of the cell cycle. Analysis of Hi-C data indicated that the Caulobacter chromosome consists of multiple, largely independent spatial domains. These domains are stable throughout the cell cycle and are reestablished concomitantly with DNA replication. We show that domain boundaries are established by actively expressed regions, and disappear when transcription is inhibited. Using polymer simulations, we build a model of a wild-type Caulobacter chromosome, and show that the Hi-C data is consistent with an array of supercoiled plectonemes arranged into a bottle brush-like fiber. We show that placing regions free of plectonemes at sites of highly expressed genes can reproduce the domain boundaries in the Hi-C map. We then performed Hi-C in bacteria under transcription inhibition, supercoiling relaxation, and depletion of a chromatin-associated HU protein. We changed our model to reproduce most prominent changes in Hi-C contact ma ps, which suggests molecular mechanisms responsible for these changes. We analyzed Hi-C data from budding and fission yeast and developed models of their chromosomal organization. We find that both yeast species are well characterized by polymer ensembles of Rabl-like chromosome conformations, where all the centromeres are bunched together at the spindle pole body. However, these genomes have very different karyotypes: budding yeast has 16 chromosomes, while fission yeast has three. For budding yeast, we find that a simple equilibrium model is consistent with Hi-C, microscopy observations and diffusion measurements of yeast chromosomes. However, S. pombe Hi-C data is poorly explained by equilibrium polymer simulations, and additional compaction constraints are needed to reproduce Hi-C data, perhaps due to the longer chromosomes in this organism. Additionally, we do not find well-defined chromosomal domains in the yeast genome. This is surprising, since domains have been observed both in bacteria and in higher eukaryotes. Taken together, our observations highlight that higher lev el chromosomal organization can be very organism-specific.

E. Kolker

Seattle Children's Research Institute

Proteomes in Profile

These days, large volumes of high-throughput mass spectrometry proteomics studies are routinely conducted. The studies are ultimately aimed at better understanding biological processes by studying proteomes' profiles. However, the size and complexity of proteomics data hinders efforts to easily share, integrate, query, and compare such profiles. We will overview our recent developments addressing these challenges, including the creation of MOPED (Model Organism Protein Expression Database, moped.proteinspire.org). MOPED focuses on answering four fundamental questions:
1. Which proteins are identified and where (organisms, tissues, localizations, pathways)?
2. How much of each protein is identified (relative and absolute expression)?
3. How does the knowledge of your current experiment compare to existing information?
4. How does this knowledge guide your next (experimental or computational) study?

Ольга Вальба

MIPT

New phase transition in random RNA-type matching

We study the fraction f of nucleotides involved in the formation of a cactus-like secondary structure of random heteropolymer RNA-like chain as a function of the number c different nucleotide species. We find, that with changing c, the secondary structures of very long random RNAs undergo a morphological transition: f=1 for cccr, meaning that an imperfect structure with finite density of gaps is formed. We show that ccr lies within the interval [2,4]. Using combinatorial methods we give the estimate c ccr?2.8, which is close to numerically obtained value.

Jerome Waldispuhl*, Yann Ponty, Vladimir Reinharz

McGill University, Canada

Exploring the RNA mutational landscape

Understanding the relationship between RNA sequences and structures is essential to decipher evolutionary processes, predict deleterious mutations and design synthetic molecules. In this talk, we introduce RNAmutants, the first algorithm for exploring RNA sequence-structures maps in polynomial time and space. Using statistical mechanics and weighted sampling techniques, we explore regions of the mutational landscape preserving the nucleotide composition and show how the GC-content influences the evolutionary accessible structural ensemble. Then, we illustrate the versatility of our techniques and apply them to (i) designing RNA sequences folding into target secondary structures, and (ii) to correcting sequencing errors in structured RNA sequences.

Edgar Wingender

University Medical Center Goettingen and geneXplain GmbH, Germany

Constructions and analysis of gene regulatory networks

Gene regulatory networks comprising transcriptional and post-transcriptional events may provide a useful tool for characterizing regulatory processes of a cell with systems biological approaches. Using bioinformatic approaches for two independent criteria (predicted affinity and multi-genome conservativity), we have constructed the core of a transcriptional network for human cells. This network was expanded (a) by paralogous TF-target gene relations, based on a comprehensive transcription factor classification, and (b) by predicted and known microRNA-target gene relations. From the resulting gene regulatory reference network, a number of tissue-specific subnetworks could be extracted. They revealed structural particularities that seem to be characteristic for the different tissues.

Сергей Владимиров (администратор русскоязычного раздела Википедии)

Википедия для образования и образование для Википедии

Что такое Википедия. Какие знания попадают в открытую и свободную онлайн-энциклопедию, и кто решает, что сохранить, а что отбросить. Можно ли с помощью Википедии рассказать о своём исследовании всему миру. Когда Википедия может оказаться полезной в образовании и когда ее использование принесит вред. Опыт использования в учебном процессе в МФТИ.

Павел Флегонтов

Институт паразитологии, Чешская академия наук, Ческе Будейовице и ИППИ РАН

Митохондриальные геномы простейших Chromera velia и Perkinsela: рекомбинация, редукция и редактирование

Chromera velia (Alveolata, Apicomplexa) - фотосинтетический организм, принадлежащий к одной из базальных ветвей группы Apicomplexa. Apicomplexa и родственные им динофлагелляты имеют наиболее редуцированные из известных митохондриальных геномов, содержащие гены cox1, cox3 и cob и сильно фрагментированные гены рРНК. Для митохондриальных геномов динофлагеллят характерна высокая концентрация повторов и активная рекомбинация, а также слабоизученное РНК-редактирование с широким спектром замен. Митохондриальный геном Chromera по данным секвенирования с помощью Illumina и 454, клонирования и ПЦР предсталяет собой огромный набор рекомбинирующих линейных молекул, в котором редукция кодирующей части идет дальше - потерян ген cob. Ядерные субъединицы комплекса цитохромов bc1 также утрачены, вследствие чего дыхательная цепь митохондрий Chromera имеет, по-видимому, уникальную организацию.
Perkinsela sp. (Euglenozoa, Kinetoplastea) - эндосимбионт амеб, малоизученный представитель базальной ветви кинетопластид. Как и Apicomplexa, группа Kinetoplastea известна в основном своими паразитическими представителями - в данном случае трипаносомами и лейшманиями. Двуядерные клетки Perkinsela содержат огромный ассоциат митохондриальной ДНК, по массе превышающий массу ядерной ДНК. Митохондриальный геном по данным секвенирования с помощью Illumina представлен линейными фрагментами с концевыми повторами. В отличие от других кинетопластид, у Perkinsela обнаружены только гены cox1, cox3 и cob, а также три неидентифицированных транскрипта, два из которых возможно представляют собой чрезвычайно дивергентные рРНК. Большинство транскриптов подвергаются массированному редактированию путем вставок и делеций U. Уридиловое редактирование у трипаносом было первым обнаруженным примером редактирования РНК, и к настоящему времени хорошо изучено. Картирование транскриптомных чтений Perkinsela показывает, что предполагаемые гены рРНК подвергаются альтернативному редактированию с образованием множества конечных продуктов.

Сергей Нуждин

Университет Южной Калифорнии, США

Population Genetics + Systems Biology = Personalized Medicine?

Understanding how environmental conditions interact with metabolic reactions, cell signaling, and developmental pathways to translate an organism's genome into its phenotype is a grand challenge in biology. Genome wide association studies (GWAS) statistically connect genotypes to phenotypes, without any recourse to known molecular interactions, whereas a molecular biology approach directly ties gene function to phenotype through gene regulatory networks (GRNs). Using natural variation in allele-specific expression, GWAS and GRN approaches can be merged into a single framework via Structural Equation Modeling (SEM). This approach leverages the myriad of polymorphisms in natural populations to elucidate and quantitate the molecular pathways that underlie phenotypic variation. The SEM framework can be used to quantitate a GRN, to evaluate its consistency across environments or sexes, to identify the differences in GRNs between species, and to annotate GRNs de novo in non-model organisms.

Василий Студитский

МГУ им М.В. Ломоносова и University of Medicine and Dentistry of New Jersey

Mechanisms of Pol II Transcription through Chromatin and Histone Chaperone FACT Action

Transcription of eukaryotic genes by RNA polymerase II (Pol II) is typically accompanied by nucleosome survival and minimal exchange of histones H3/H4 carrying epigenetic marks. In some cases, nucleosomes present high, regulated barrier to transcribing Pol II. Recently we have shown that efficient transcription through a nucleosome is coupled with formation of an intermediate (a small intranucleosomal DNA loop (O-loop) containing transcribing Pol II complex) that guarantees nucleosome survival during transcription. Histone chaperone FACT affects the efficiency of both processes (transcription through chromatin and nucleosome survival), most likely affecting the efficiency of formation of the O-loop. The mechanism of FACT action during transcription through chromatin will be presented.

Дмитрий Первушин

ФББ МГУ им М.В. Ломоносова, Centre for Genomic Regulation, Barcelona

Вторичная структура и процессинг пре-мРНК: исследование методами сравнительной геномики

Задача предсказания вторичной структуры РНК по нуклеотидной последовательности появилась на заре биоинформатики в 70-е годы и стала очень популярна благодаря тому, что в ней содержится увлекательная комбинаторная часть - поиск обращенных палиндромов. Для коротких структурированных последовательностей она хорошо решается методом динамического программирования. Существует также другая группа методов, основаная на сравнении родственных последовательностей. Одновременное выравнивание последовательностей РНК и предсказание их вторичной структуры может быть решено динамическим программированием за время O(n^6), но даже в максимально упрощеном виде алгоритм остается слишком сложным для полногеномных исследований. Однако основная проблема заключается не в степени алгоритма, а в том, что с увеличением n он начинает работать неправильно из-за запрета на псевдоузлы. В докладе будет представлен новый, основанный на комбинаторных трюках, метод нахождения консервативных комплементарных участков РНК, не имеющий запрета на псевдоузлы. Также будет рассказано о консервативных структурах РНК, предположительно участвующих в регуляции событий альтернативного сплайсинга и альтернативного полиаденилирования у млекопитающих, дрозофил, и нематод. В большинстве случаев эти структуры отличаются от классических шпилечных структур именно длиной петли - она может достигать нескольких килобаз. Также будет рассказано о предсказании межмолекулярных РНК-РНК взаимодействий и о том, какие результаты дают эти предсказания для классов длинных некодирующих РНК и белок-кодирующих РНК.

Olga V. Kalinina

Max Planck Institute for Informatics, Saarbrucken, Germany & IITP

Sequence and structure approaches in bioinformatics of HIV

Human immunodeficiency virus causes AIDS, and hence presents a major health hazard worldwide. Genotyping of HIV positive patients has become a common practice in many countries. Statistical analysis of the collected data allows for successful prediction of most effective treatment to avoid the acquired drug resistance mutations and take into account virus tropism to co-receptor, but the structural and mechanistic basis remains unknown. Thus HIV presents a challenging target for combining sequence-driven and structure-driven bioinformatics approaches to gain new functional insights. Several case studies involving HIV capsid, envelope and protease proteins will be discussed.

Иоахим Мессинг

Университет Ратгерс

История секвенирования ДНК методом дробового ружья

Joachim Messing

Waksman Institute of Microbiology, Rutgers University

History of Shotgun DNA Sequencing

Recently, the Wharton School ranked DNA sequencing behind the Internet, Cell Phone, Email, and Laptop Computers the greatest innovation of our times. However, it is not so much by which method short strings of nucleotides are sequenced than the concept of parallelization of sequencing reactions that have revolutionized the sequencing of entire genomes. Parallelization of sequencing is based on universal primers and has been greatly accelerated by automation and computational capacity in recent years. This work began nearly 25 years ago with the construction of single-stranded phage (M13mp series) and high-copy plasmid (pUC series) vectors with their host strains (JM series) to today's next generation sequencing efforts.

Михаил Спиваков

Европейский биоинформатический институт

Путеводитель по проекту ENCODE

Alex Abyzov

Yale University

Using Sequencing for Detection of Genomic Structural Variations in Human Cells

Genomic structural variations (SVs) is a complex phenomenon, and not completely understood. Though abundant in humans, SVs differ from other forms of variation in extent, origin and functional impact. SVs have been linked to cancer, as well as inherited and mendelian diseases. The wealth of recent genomic sequencing data allows studying SVs on an unprecedented scale (from the analysis of large populations to understanding somatic variations within a single individual) and with unprecedented accuracy (often with single base pair resolution of breakpoints). In my seminar, I will describe several complementary methods that I developed to discover SVs using sequence data, along with their advantages and limitations. I will then demonstrated how identifying SVs and constructing a personal diploid genome server as a basis for unbiased functional analyses, lead to generation of biological hypothesis about cell processes, allow for understanding of the stability of iPSC genomes, and enable evaluation of the extent of somatic SVs in individual cells. http://homes.gersteinlab.org/people/aabyzov

Mark Reimers

Virginia Institute for Psychiatric and Behavioral Genetics, VCU School of Medicine

Gene Expression in the Human Brain: Insights from Genomic Profiling of the Human Brain

The BrainSpan project aims to comprehensively study the genomic program of human brain development and how this differs from non-human primates. Drawing on this project (on which the speaker collaborates) and data from other research groups, the speaker will present some new discoveries about human brain development, evolution and individual differences, including psychiatric disorders, as revealed by genomic profiling. http://www.people.vcu.edu/~mreimers/
Семинар пройдет при поддержке фонда "Династия".

Yannis Kalaidzidis

Max Planck Institute of Molecular Cell Biology and Genetics (Dresden)

Multiscale computational approach to systems biology

Systems biology aims at the understanding of how many different molecules work together to build cells, organs and, ultimately, an entire organism. Understanding of a biological system in terms of its engineering properties and functional circuitries allows predicting how a given perturbation, such as a disease or drug, can impact on the physiology of an organism. In the past two decades, the sequencing of various genomes in combination with a number of analytical technologies (omics) has enabled the systematic analysis of cellular components. Functional genomics techniques (e.g. RNA interference, RNAi) applied at large scale have addressed the function of individual genes with respect to a particular cellular process. Cataloguing the individual molecules expressed in a cell is, however, not sufficient to reconstruct the mechanisms whereby individual molecules interact in functional networks or assemble into organelles to form cells and tissues. The present modelling approaches largely focusing on signal transduction and metabolic pathways can capture the complexity of cell and tissue organization only to a very limited degree. One of the reasons why cell and tissue morphogenesis remains an unsolved problem is that we lack detailed and accurate information on the spatio-temporal patterns of molecules (the where and when) in the context of their function in cells and tissues.
Light microscopy is a major source of detailed information on spatio-temporal organization of biological systems, ranging from single molecule to sub-cellular structures up to whole organ level. In recent years, light microscopy techniques have been developed to such an extent that they can now provide an unprecedented level of resolution, dynamic range and throughput for the imaging and analysis of biological samples.
For example, imaging and quantifying cellular organelles such as endosomes is a major challenge. Endosomes range in size between 100nm and 1-2?m (Fig.1) and the amount of specific molecular components can vary more then 2-3 orders of magnitude. Although image processing is being done in biology, many of the techniques used are still inadequate to extract quantitative parameters from image data, which can be used to generate mathematical models of biological processes on different scales.
When applied to high-throughput studies, this technology has the potential to explore the complexity of cellular circuits and discriminate between possible mathematical models by testing their predictions.

Marco Faini

European Molecular Biology Laboratory (Heidelberg)

The structures of COPI-coated vesicles reveal alternate coatomer conformations and interactions

Transport between compartments of eukaryotic cells is mediated by coated vesicles. The archetypal protein coats COPI, COPII and clathrin are conserved from yeast to human. Structural studies of COPII and clathrin coats assembled in vitro without membranes suggest that coat components assemble regular cages with the same set of interactions between components. Detailed 3D structures of coated vesicles with membranes have not been obtained. Here, we solved the structures of individual COPI-coated membrane vesicles by cryo-electron tomography and subtomogram averaging of in vitro reconstituted budding reactions. The coat protein complex, coatomer, was observed to adopt alternative conformations to change the number of other coatomers with which it interacts, and form vesicles with variable sizes and shapes. This represents a fundamentally different basis for vesicle coat assembly.

Вадим Гладышев

Harvard Medical School

Анализ редокс-регуляции и старения через анализ геномов

Nearly every cellular system is subject to reduction-oxidation (redox) control. Thiol-based redox regulation emerged as a key redox system that acts through the redox state of cysteine residues in proteins. We developed tools for identification of thiol oxidoreductases on a redox-wide scale and found that these proteins account for approximately 1% of the proteome and are present in all living organisms. A subset of these proteins utilizes catalytic redox selenocysteine residues. One animal poses a challenge to the understanding of redox homeostasis. This animal, naked mole rat (NMR), is characterized by significant oxidative stress, but its proteome does not show age-related susceptibility to oxidative damage nor increased ubiquitination. Although the size of a mouse, NMR's maximum lifespan exceeds 30 years making this animal the longest living rodent. NMRs show negligible senescence, no age-related increase in mortality, and high fecundity until death. In addition to delayed aging, NMRs are resistant to spontaneous cancer. We sequenced and analyzed the NMR genome, which revealed unique genome features and molecular adaptations consistent with cancer resistance, poikilothermy, hairlessness, altered visual function, circadian rhythms and taste sensing. The extreme traits of NMR, together with the genome and transcriptome information, offer opportunities for understanding aging and redox biology, and advancing many other areas of biological and biomedical research.

Vasily M. Studitsky

School of Biology, MSU and UMDNJ-Robert Wood Johnson Medical School

Mechanisms of Gene Regulation Over a Distance on DNA and in Chromatin

The majority of eukaryotic genes and some prokaryotic genes are positively regulated by activator-binding DNA sequences (enhancers) that can efficiently communicate and directly interact with their targets (promoters) over extended regions of spacer DNA organized into chromatin structure (see (1) for a review). The mechanisms that mediate enhancer-promoter interaction in chromatin include tracking and looping models.
Previously we have shown that DNA supercoiling greatly facilitates EPC over a large distance (2-4). Our studies have also suggested that chromatin structure per se can support highly efficient communication over a distance by a looping mechanism and functionally mimic the supercoiled state characteristic for prokaryotic DNA (5). However, the mechanisms allowing efficient communication in chromatin remain unknown.
More recently, we have established defined polynucleosomal chromatin templates allowing quantitative analysis of the rate of distant EPC and have identified components of the system and protein factors that strongly affect the rate of communication in chromatin. These studies will be presented at the seminar.

Yuri Pritykin and Mona Singh

Department of Computer Science and Lewis-Sigler Institute for Integrative Genomics, Princeton University

Date and party hubs across organisms

In Han et al. (Nature 430, 88-93 (2004) doi:10.1038/nature02555), the classification of hubs (genes involved in many protein-protein interactions) to "date" and "party" was proposed. It was based on the average co-expression of a gene with its interacting partners in the protein-protein physical interaction network (measured using a compendium of microarray expression experiments across different conditions and timepoints). Although this classification has been highly influential in the literature, its biological relevance caused some controversy. We argue in favor of this classification. Using recent interaction and expression data, we show that the distinction between two types of hubs is supported across five different organisms, including three for which it was not previously tested, and moreover, is conserved between organisms.