Conferences system

Четверг, 23 января 2013 года, 18:00, Москва, МГУ, лабораторный корпус «Б».

Тема заседания — доклад Максима Имакаева MIT
«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 (Saccharomyces cerevisiae) and fission (Schizosaccharomyces 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 maps, 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 level chromosomal organization can be very organism-specific

Рабочий язык семинара — русский.

Адрес:
Москва, МГУ, лабораторный корпус «Б» (факультет биоинженерии и биоинформатики), комната 221 (2 этаж, от лестницы направо по коридору).
Проезд: Станция метро Университет, автобусы 187, 260, 130, 103, 113, 661, 47 или троллейбус 34 до остановки: «Улица Менделеевская».
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