Revealing chromatin state organization on the single-molecule scale
Van Leeuwenhoek Lecture on BioScience.
Beat Fierz studied Molecular Biology at the Biozentrum of the University of Basel (1998-2001). He then became interested in quantitative aspects of biology and obtained a Diploma in Biophysical Chemistry (2002). Subsequently, he performed his PhD studies (2002-2006) in Professor Kiefhaber's lab at the Biozentrum, where he investigated the dynamics of synthetic polypeptides and protein secondary structure elements using ultrafast time-resolved spectroscopy. In 2007 he joined the laboratory of Professor Muir at the Rockefeller University, New York and later Princeton University, New Jersey. There, he studied the folding behavior of chromatin fibers as well as the stability of nucleosome particles, depending on histone post-translational modifications. In 2012, Beat Fierz was appointed Tenure Track Assistant Professor for the newly created Chaire Foundation Sandoz en Chimie Biophysique des Macromolecules.
The research of Beat Fierz focuses on the study of the structure, dynamics and function of chromatin and related multi-protein complexes in vitro and in cells. These investigations require an interdisciplinary approach at the interface of chemistry, biology and biophysics.
The dynamic organization of the eukaryotic genome into chromatin is integral to genome regulation. Chromatin structure and dynamics dictate DNA access for the nuclear machinery, thereby controlling gene expression, DNA repair and replication processes. Local DNA accessibility is further modulated by patterns of histone post-translational modifications (PTMs), acting together with architectural effector proteins to establish a functional chromatin state.
The dynamic architecture of chromatin fibers dependent on PTM paterns and effector proteins is however poorly understood, due to a lack of methods suitable to study large heterogeneous complexes. We addressed this challenge by combining convergent synthesis of chemically defined and precisely fluorescently labeled chromatin fibers with multimodal single-molecule FRET measurements. This allowed us to directly uncover chromatin toplogy and to measure dynamic processes within compact fibers from microseconsds to seconds.
We find that local chromatin structure is organized in tetranucleosome units, whose interaction patterns interchange in concerted motions within milliseconds. Structural effectors, such as linker histone H1 and PTM dependent binders HP1 critically influence local structure and dynamics, transiently stabilizing nucleosome interactions, but conserve a highly dynamic chromatin state. Together, our studies thus demonstrate that chromatin fibers are structurally heterogeneous and highly dynamic, forming local transient structures that regulate the function of downstream effector proteins but are still permissive for chromatin change.