Abstract
Phospholipase C (Plc1p) is required for the initial step of inositol polyphosphate (InsP) synthesis, and yeast cells with deletion of the PLC1 gene are completely devoid of any InsPs and display aberrations in transcriptional regulation. Here we show that Plc1p is required for a normal level of histone acetylation; plc1Δ cells that do not synthesize any InsPs display decreased acetylation of bulk histones and global hypoacetylation of chromatin histones. In accordance with the role of Plc1p in supporting histone acetylation, plc1Δ mutation is synthetically lethal with mutations in several subunits of SAGA and NuA4 histone acetyltransferase (HAT) complexes. Conversely, the growth rate, sensitivity to multiple stresses, and the transcriptional defects of plc1Δ cells are partially suppressed by deletion of histone deacetylase HDA1. The histone hypoacetylation in plc1Δ cells is due to the defect in degradation of repressor Mth1p, and consequently lower expression of HXT genes and reduced conversion of glucose to acetyl-CoA, a substrate for HATs. The histone acetylation and transcriptional defects can be partially suppressed and the overall fitness improved in plc1Δ cells by increasing the cellular concentration of acetyl-CoA. Together, our data indicate that Plc1p and InsPs are required for normal acetyl-CoA homeostasis, which, in turn, regulates global histone acetylation.
Highlights
Glucose metabolism provides acetyl-CoA for histone acetylation
Our results suggest that histone hypoacetylation in plc1⌬ cells affects the spread of Sir3p from heterochromatin regions, and are consistent with a previous study [49] that showed that two main histone acetyltransferase (HAT), SAGA and NuA4, are required for proper acetylation of nucleosomes in the HMR and telomere-proximal genes and that mutation in NuA4 severely affects the boundary function
Our results show that Plc1p and Inositol polyphosphates (InsPs) are important for the normal level of histone acetylation
Summary
Results: Inositol polyphosphates (InsPs), produced by the phospholipase C-dependent pathway, are required for degradation of the transcriptional repressor Mth1p, expression of glucose transporters, and normal acetyl-CoA homeostasis. Phospholipase C (Plc1p) is required for the initial step of inositol polyphosphate (InsP) synthesis, and yeast cells with deletion of the PLC1 gene are completely devoid of any InsPs and display aberrations in transcriptional regulation. We show that Plc1p is required for a normal level of histone acetylation; plc1⌬ cells that do not synthesize any InsPs display decreased acetylation of bulk histones and global hypoacetylation of chromatin histones. Plc1⌬ mutation is synthetically lethal with mutations in the SAGA and NuA4 complexes, the major yeast HATs. deletion of histone deacetylase HDA1 partially suppressed the slow growth phenotype and improved overall fitness of plc1⌬ cells. Our data show that InsPs affect histone acetylation and transcriptional regulation by a mechanism that involves regulation of the acetyl-CoA homeostasis
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