Smad5 acts as an intracellular pH messenger and maintains bioenergetic homoeostasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE99687 | GEO | 2017/11/01
SECONDARY ACCESSION(S): PRJNA389303
REPOSITORIES: GEO
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Project description: Not available
| S-EPMC5587853 | biostudies-literature
Project description:Differences in global levels of histone acetylation occur in normal and cancer cells, although the reason cells regulate these levels has remained unclear. Here we demonstrate a role for histone acetylation in regulating intracellular pH (pHi). As pHi decreases, histones are globally deacetylated by histone deacetylases (HDACs) and the released acetate anions are co-exported with protons out of the cell by monocarboxylate transporters (MCTs), preventing further reductions in pHi. Conversely, global histone acetylation increases at more alkaline pHi, such as when resting cells are induced to proliferate. Inhibition of HDACs or MCTs decreases acetate export and lowers pHi, particularly compromising pHi maintenance in acidic environments. Global deacetylation at low pH is reflected at a genomic level by decreased abundance and extensive redistribution of acetylation at promoters and intergenic regions. Thus acetylation of chromatin functions as a rheostat to regulate pHi with important implications for therapeutic use of HDAC inhibitors. To investigate the redistribution of H4K16ac throughout the genome upon treatment at pH 6.5
2012-11-04 | E-GEOD-40114 | biostudies-arrayexpress
Project description:Differences in global levels of histone acetylation occur in normal and cancer cells, although the reason cells regulate these levels has remained unclear. Here we demonstrate a role for histone acetylation in regulating intracellular pH (pHi). As pHi decreases, histones are globally deacetylated by histone deacetylases (HDACs) and the released acetate anions are co-exported with protons out of the cell by monocarboxylate transporters (MCTs), preventing further reductions in pHi. Conversely, global histone acetylation increases at more alkaline pHi, such as when resting cells are induced to proliferate. Inhibition of HDACs or MCTs decreases acetate export and lowers pHi, particularly compromising pHi maintenance in acidic environments. Global deacetylation at low pH is reflected at a genomic level by decreased abundance and extensive redistribution of acetylation at promoters and intergenic regions. Thus acetylation of chromatin functions as a rheostat to regulate pHi with important implications for therapeutic use of HDAC inhibitors.
2012-11-04 | GSE40114 | GEO
Project description:Emerging evidence is revealing critical roles of intracellular pH (pHi) in development (), but it remains unclear whether pHi regulates adult stem cell lineage specification. We find that pHi dynamics is a key regulator of cell fate in the mouse intestinal stem cell (ISC) lineage. We identify a pHi gradient along the crypt axis in intestinal organoids and find that dissipating this gradient by inhibiting Na-H exchanger 1 (NHE1) activity genetically or pharmacologically abolishes crypt budding. Using lineage tracing and single cell RNA sequencing we demonstrate that pHi dynamics acts downstream of Atoh1, with increased pHi promoting differentiation toward the secretory lineage, while reduced pHi biases differentiation into absorptive lineage. Consistent with this, disrupting the pHi gradient blocks new Paneth cell differentiation. Paneth cells provide an essential Wnt signal to ISCs in organoids, and we find that the loss of crypt budding upon NHE1 inhibition can be rescued with exogenous WNTs. Altogether, our findings indicate that pHi is tightly regulated in the ISC lineage and that an increase in pHi is required for Paneth cell specification and thus tissue maintenance. These observations reveal a previously unrecognized role for pHi dynamics in the cell fate specification within an adult stem cell lineage.
2023-05-10 | GSE211097 | GEO
Project description:The BMP signaling pathway regulates multiple steps of hematopoiesis, mediated through receptor-regulated Smads, including Smad1 and Smad5. Here we use loss-of-function approaches in zebrafish to compare the roles of Smad1 and Smad5 during embryonic hematopoiesis. Microarray experiments revealed that the two proteins regulate redundantly the key initiators of the hemato-vascular program, including scl, lmo2, and gfi1. However, each also regulates a remarkably distinct genetic program, with Smad5 uniquely regulating the BMP signaling pathway itself. Our results suggest that specificity of BMP signaling output, with respect to hematopoiesis, can be explained by differential functions of Smad1 and Smad5. Keywords: Gene expression transcript profiles The experiment was designed to identify the unique Smad1 and Smad5 dependent transcripts during the somitogenesis stage of development, during which mesoderm is specified to the hematopoietic lineage. Embryos were injected with translational blocking morpholinos for Smad1, Smad5 or both, and then collected at the 1-somite stage for RNA extraction. For every experiment control uninjected wildtype sibling embryo were also collected for comparison. Three biological replicates were done for each knockdown set. Total RNA was sent to Nimblegen for cDNA synthesis, dye labeling and hybridization. Single knockdown samples were hybridized to the Nimblegen 2006 Danio rerio Gene Expression Array chip and the double knockdown samples to the 2007 verison of the chip, which contains the same test genes, but with additional control oligos. Dye swaps were done for each set; for 2 of the 3 hybridization in each set Cy3 was the dye used for the experimental sample and in the 3rd Cy5 was used. The raw hybridization data was obtained from Nimblegen, normalized using NimbleScan and anaylzed using R software.
2010-06-25 | E-GEOD-8903 | biostudies-arrayexpress
Project description:The BMP signaling pathway regulates multiple steps of hematopoiesis, mediated through receptor-regulated Smads, including Smad1 and Smad5. Here we use loss-of-function approaches in zebrafish to compare the roles of Smad1 and Smad5 during embryonic hematopoiesis. Microarray experiments revealed that the two proteins regulate redundantly the key initiators of the hemato-vascular program, including scl, lmo2, and gfi1. However, each also regulates a remarkably distinct genetic program, with Smad5 uniquely regulating the BMP signaling pathway itself. Our results suggest that specificity of BMP signaling output, with respect to hematopoiesis, can be explained by differential functions of Smad1 and Smad5. Keywords: Gene expression transcript profiles
2008-08-22 | GSE8903 | GEO
Project description:Recent studies have linked bioenergetic regulation to cellular differentiation. However, the contribution of metabolic communication among subcellular components to the fate of progenitor cells remains unclear. Adenylate kinase 2 (AK2) is an adenylate phosphotransferase localized in the mitochondrial intermembrane space. Although AK2 mutations in human can cause a severe combined immunodeficiency with neutropenia, named reticular dysgenesis (RD), underlying mechanisms have not yet been elucidated. To address these questions, we established induced pluripotent stem cells (iPSCs) from two RD patients. Metabolic flux analysis revealed that AK2 mediates the distribution of glycolytic metabolites into the tricarbon acid cycle in mitochondria. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. Intriguingly, RD-iPSC-derived hematopoietic progenitors exhibited an immature mitochondrial morphology, discordant ATP distribution among the mitochondria and nucleus, and alteration of global transcriptional profiles. These results highlight the importance of stage-specific intracellular energy communication for controlling the fate of multipotential progenitors.
2018-09-03 | GSE76761 | GEO
Project description: Not available
| S-EPMC1201361 | biostudies-literature
Project description:Mice deficient in the BMP-effector, Smad5 (Smad5 KO), develop severe defects in embryonic morphogenesis as well as a delay in amnion-chorion separation, important extraembryonic tissues. After closure of the proamniotic canal, a remarkable ectopic primitive streak-like aggregate develops in the amnion of these mutants. We investigated the earliest steps of mutant amnion misdifferentiation by RNAseq of single Control (Ctrl) and Smad5 KO amnion samples collected before the appearance of the aggregate. The transcriptome analysis revealed two separate sets of non-squamous amnion defects. One set of mutants (KO-SetA) robustly overexpressed streak mesoderm-related genes conform former analyses (Pereira et al., 2012). The other set overexpressed extraembryonic ectoderm markers suggestive of chorionic inclusion in amnion (KO-SetB). Tetraploid chimera analyses confirmed that SMAD5 deficiency in the epiblast can result in two distinct sets of amnion defects: one with impaired anterior amnion expansion and differentiation, and another with inclusion of chorionic extraembryonic ectoderm in the space normally occupied by amnion.
2018-06-15 | GSE99211 | GEO
Project description:In this study we determine the transcriptional profile by RNAseq of mESC in the absence of Smad1 and Smad5 and in subpopulation of mESC with different levels of BMP-SMAD activation.
2015-12-21 | GSE71554 | GEO