Engineering chromatin states: chemical and synthetic biology approaches to investigate histone modification function.
Patterns of histone post-translational modifications (PTMs) and DNA modifications establish a landscape of chromatin states with regulatory impact on gene expression, cell differentiation and development. These diverse modifications are read out by effector protein complexes, which ultimately determine their functional outcome by modulating the activity state of underlying genes. From genome-wide studies employing high-throughput ChIP-Seq methods as well as proteomic mass spectrometry studies, a large number of PTMs are known and their coexistence patterns and associations with genomic regions have been mapped in a large number of different cell types. Conversely, the molecular interplay between chromatin effector proteins and modified chromatin regions as well as their resulting biological output is less well understood on a molecular level. Within the last decade a host of chemical approaches has been developed with the goal to produce synthetic chromatin with a defined arrangement of PTMs. These methods now permit systematic functional studies of individual histone and DNA modifications, and additionally provide a discovery platform to identify further interacting nuclear proteins. Complementary chemical- and synthetic-biology methods have emerged to directly observe and modulate the modification landscape in living cells and to readily probe the effect of altered PTM patterns on biological processes. Herein, we review current methodologies allowing chemical and synthetic biological engineering of distinct chromatin states in vitro and in vivo with the aim of obtaining a molecular understanding of histone and DNA modification function. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.
Fondation Sandoz Chair in Biophysical Chemistry of Macromolecules, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Horst
H
Pick
Fondation Sandoz Chair in Biophysical Chemistry of Macromolecules, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Sinan
S
Kilic
Fondation Sandoz Chair in Biophysical Chemistry of Macromolecules, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Beat
B
Fierz
D000107:Acetylation; D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D058207:Sumoylation; D014158:Transcription, Genetic; D054875:Ubiquitination
D002843:Chromatin; D006657:Histones; D004247:DNA
Chromatin-associated effectors; Designer chromatin; Epigenetics; Histone post-translational modifications; Protein chemistry; Synthetic biology