Community Research and Development Information Service - CORDIS



Project ID: 340712
Funded under: FP7-IDEAS-ERC
Country: Israel

Mid-Term Report Summary - CHROMATINSYS (Systematic Approach to Dissect the Interplay between Chromatin and Transcription)

We are all familiar with the analogy of DNA as the “blue print” of life. One of the greatest challenges in biology is to understand how living cells read these complex instructions. In particular, how do cells turn the proper genes to “ON” or “OFF” at the right timing? This transcriptional regulation is critical to all forms of life from microorganisms to humans, and is established by several levels of regulatory mechanisms. During the last two decades we learned the importance of mechanisms that use chromatin, the packaging of DNA inside the cells, as a substrate. A large literature established that this packing could be marked at individual DNA locations by a wide range of different marks. These marks can be recognized by other proteins, which in turn can affect how other regulatory proteins access the DNA at the specific locality. Thus, similar to the way marking on boxes can influence where and how they are shipped, the marking on chromatin can influence how the DNA at that particular location is accessed and used. The discovery of multiple different marks and numerous “writer” and “reader” proteins, suggested that cells can use annotations over the DNA sequence that is effectively unmodified during the life of a cell or an organism as local memory of past decisions. This memory can be both short term (minutes) or long term (over generations).
In the recent years, advances in genomics led to comprehensive mapping of the chromatin marks in a range of tissues and organisms. These maps established the tight connection between these marks and regulatory programs. These static charts, however, are less successful at uncovering the underlying mechanisms, logic, and function of chromatin marks in establishing and maintaining transcriptional programs. Our premise is that we can answer these basic questions by observing the effect of genetic perturbations, where we remove one or more writer/readers, on the dynamics of both chromatin mark and transcriptional activity. We aim to study the chromatin-transcription system in a systematic manner by building on our extensive experience in modeling and analysis, and a unique high-throughput experimental system we established in my lab.
During the first half of the project we made significant advances toward these goals. We published two manuscripts reporting on large-scale experiments tracking the dynamics of chromatin marks throughout the genome in two scenarios. The first is developmental dynamics, in which hematopoietic stem cells develop into differentiated blood cells. The same stem cells can develop into a whole range of cells through a series of transformations. We characterized the chromatin marks in cells at all the intermediate stages of differentiation. The second system involves rapid response to an environmental stimulus. In this system we measured chromatin marks every few minutes. In both cases, the detailed characterization of chromatin dynamics allowed us to elucidate principles involved in the responses, and gain new insights, about specific regulatory mechanisms. In parallel we invested in developing experimental assays to improve our ability to measure chromatin structure. These include two publications, one on a methodology for tracing the 3D contacts between non-adjacent locations along the DNA, and methods for assaying combination of marks on the same location.

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