Project description:Differing levels of chromatin compaction throughout the genome contribute to cell specificity and function. The importance of studying this complex processes is highlighted by the frequency of chromatin dysregulation in human diseases, which has led to the development of chromatin-based therapies in the clinic. To study this pathway, we designed a novel chemical-based system to redirect specific chromatin modifying machinery in a targeted and reversible manner. We synthesized a new class of bi-functional compounds, Chemical Epigenetic Modifiers (CEM)s, with one warhead arm that engages endogenous chromatin regulators, while the other targeting arm tethers the captured epigenetic regulatory machinery to the gene of interest. By redirecting endogenous chromatin regulatory machinery, we are able to control expression in a gene-specific manner.
Project description:To treat obesity and its related metabolism, small molecules can be used. To investigate the role of small molecules, butein, sulfuretin, and resveratrol were treated in differentiated adipocytes to find important regulators in adipocyte biology. Each small molecules have their own charactaristics on adipocyte biology, comparison of expression profiles among three small molecules can offer new insight in adipocyte biology.
Project description:This SuperSeries is composed of the following subset Series: GSE37611: Effect of small molecules on activated astrocytes GSE37612: Effect of small molecules on activated BV2 microglia cell line Refer to individual Series
Project description:Time course micro array experiment to identify transcriptional changes in response to exposure of hFLs to different combinations of small molecules during direct neuronal reprogramming hFL1 cells were transduced with conversion factors Ascl1, Brn2a and Myt1L and five days after transduction, transgene expression was activated by doxycycline. On day 3 of transgene expression, MEF medium was replaced by N2B27 medium plus small molecules, depending on the condition. Ascl1 expression was linked to GFP so that all GFP pos cells were FACS isolated at different times of exposure to small molecules (or N2B27 medium in transgene only groups). Post FACS, cells were lysed and total RNA was extracted and used as input for micro array experiments.
Project description:Small molecules directly binding DNA in cells destabilized chromatin what is "sensed" by histone chaperone FACT. FACT binds regions with destabilized chromatin via "c-trapping". DNA-targeting small molecules are widely used for anticancer therapy based on their ability to induce cell death, presumably via DNA damage. DNA in the eukaryotic cell is packed into chromatin, a highly-ordered complex of DNA, histones, and non-histone proteins. These agents perturb chromatin organization. However, the mechanisms, consequences, and impact of the alterations of chromatin structure in relation to their anti-cancer activity is unclear because it is difficult to separate DNA damage and chromatin damage in cells. We recently demonstrated that curaxins, small molecules with broad anticancer activity, bind DNA without causing detectable DNA damage by interfering with histone/DNA interactions and destabilizing the nucleosome. Chromatin unfolding caused by curaxins is sensed by histone chaperone FACT. FACT binds unfolded nucleosomes, which leads to chromatin trapping or c-trapping. In this study, we investigated whether other DNA-targeting small molecules disturb chromatin and cause c-trapping. We found that only compounds directly binding DNA induce chromatin damage and c-trapping. Chromatin damage may occur in the absence of DNA damage and is dependent on the mechanism of compound binding to DNA and its ability to bind chromatinized DNA in cells. We show that FACT is sensitive to a plethora of nucleosomes perturbations induced by DNA-binding small molecules, including displacement of the linker histone, eviction of core histones, and accumulation of negative supercoiling. Most importantly, the cytotoxicity of DNA-binding small molecules correlates with their ability to cause chromatin damage, but not DNA damage.
Project description:Time course micro array experiment to identify transcriptional changes in response to exposure of hFLs to different combinations of small molecules during direct neuronal reprogramming