Project description:We report the nuclear Gcn5/α-KGDH complex plays vital role in histone H3 K79 succinylation. By obtaining over 731 million reads from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of histone H3 K79 succinylation, Gcn5, and α-KGDH in U251 cells.
Project description:Lysine succinylation is one of the major post-translational modifications occurred on histones and is believed to have significant roles in regulation of chromatin structure and function. Currently, histone desuccinylation is widely believed to be exerted by the members of SIRT family deacetylases. Here, we report that histone desuccinylation is in fact primarily catalyzed by the class I HDAC1/2/3. Inhibition or depletion of HDAC1/2/3 resulted in marked increase of global histone succinylation, whereas ectopic expression of HDAC1/2/3 but not their deacetylase inactive mutants downregulated global histone succinylation. We demonstrated that the class I HDAC1/2/3 complexes have robust histone desuccinylase activity in vitro. Genomic landscape analysis revealed that histone succinylation is highly enriched at gene promoters and inhibition of HDAC activity results in marked elevation of promoter histone succinylation. Furthermore, integrated analysis revealed that the promoter histone succinylation positively correlates with the transcriptional activity. Collectively, we demonstrate that the class I HDAC1/2/3 but not the SIRT family proteins are the major histone desuccinylases particularly important for promoter histone desuccinylation. Our study thus sheds new light on the role of histone succinylation in transcriptional regulation.
Project description:Lysine succinylation (Ksucc) as an evolutionarily conserved and widespread post-translational modification has been identified. However, the mechanism of succinylation modulation remains unclear. Here, we report a histone acetyltransferase is a succinyltransferase, essentially enhancing the tumor growth and metastasis.
Project description:Krüppel-like factors (KLFs) are a group of master regulators of gene expression conserved from flies to human. However, scant information is available on either the mechanisms or functional impact of the coupling of KLF proteins to chromatin remodeling machines, a deterministic step in transcriptional regulation. In the current study, we use genome-wide analyses of chromatin immunoprecipitation (ChIP-on-Chip) and Affymetrix-based expression profiling to gain insight into how the KLF11, a human transcription factor involved in tumor suppression and metabolic diseases, works by coupling to three co-factor groups: the Sin3-histone deacetylase system, WD40-domain containing proteins, and the HP1-histone methyltransferase system. We utilized genome-wide expression analysis of wild type KLF11 and three mutants that disrupt KLF11-chromatin machinery interactions to examine the relationship of the transcription factor and chromatin systems in the regulation of gene networks.
Project description:Krüppel-like factors (KLFs) are a group of master regulators of gene expression conserved from flies to human. However, scant information is available on either the mechanisms or functional impact of the coupling of KLF proteins to chromatin remodeling machines, a deterministic step in transcriptional regulation. In the current study, we use genome-wide analyses of chromatin immunoprecipitation (ChIP-on-Chip) and Affymetrix-based expression profiling to gain insight into how the KLF11, a human transcription factor involved in tumor suppression and metabolic diseases, works by coupling to three co-factor groups: the Sin3-histone deacetylase system, WD40-domain containing proteins, and the HP1-histone methyltransferase system. We utilized genome-wide expression analysis of wild type KLF11 and three mutants that disrupt KLF11-chromatin machinery interactions to examine the relationship of the transcription factor and chromatin systems in the regulation of gene networks. Panc1 epithelial cells were plated at a density of 1x10^6 cells/100mm dish and transduced with empty vector, KLF11, KLF11-A347S, KLF11-486, or KLF11-EAPP adenovirus at an MOI of 150. RNA was prepared as previously described from pooled biological triplicates.
Project description:Several aryl hydrocarbon receptor (AhR)-active pharmaceuticals were screened as inhibitors of pancreatic cancer cell invasion and identified two compounds, omeprazole, that inhibited invasion. Inhibition of highly invasive Panc1 cell invasion by omeprazole involves an AhR-dependent non-genomic pathway, and omeprazole-mediated inhibition of Panc1 cell invasion was dependent on Jun-N-terminal kinase (JNK) and mitogen-activated kinase kinase 7 (MKK7). The failure of omeprazole to induce nuclear translocation of the AhR was not due to overexpression of cytosolic AhR partner proteins Hsp90 or XAP2, and results of DNA sequencing show that the AhR expressed in Panc1 cells was not mutated. Results of RNAseq studies indicate that omeprazole induced an AhR-dependent downregulation of several pro-invasion factors including activated leukocyte cell adhesion molecule (ALCAM), long chain fatty acid CoA-synthase (CSL4), stathmin 3 (STMN3) and neuropillin 2 (NRP2), and the specific functions of these genes are currently being investigated.
Project description:To analyze the gene expression profile of BAT and gWAT from Pgam1 depletion mice, we performed whole genome microarray expression profiling using brown adipose tissue (BAT) and gonadal white adipose tissue (gWAT) from adipose tissue-specific Pgam1 knockout (KO) mice.