Novel Alterations in Chromatin Structure during Aging Reveal Cell-Specific Differential Expression of SUMO Proteins
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ABSTRACT:
PROVIDER: PRJNA414604 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6181360_1.fastq.gz | Fastqsanger.gz | |||
| SRR6181360_2.fastq.gz | Fastqsanger.gz | |||
| SRR6181370_1.fastq.gz | Fastqsanger.gz | |||
| SRR6181370_2.fastq.gz | Fastqsanger.gz | |||
| SRR6181361_1.fastq.gz | Fastqsanger.gz |
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Project description:We investigated the chromatin accessibility of primary human adipose-derived stem cells (ASCs) and fibroblasts during chronological aging using ATAC-seq technology. our data suggest a significant role for nucleosome positioning in sumoylation pathway regulation in response to stress during aging of adult stem cells.
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Project description:Most SUMO-modified proteins in budding yeast and human cells are associated with chromatin. To determine specifically where sumoylated proteins are found across the genome, we performed ChIP-seq with a SUMO antibody in budding yeast. We identified 603 loci that each contain a stable SUMO peak. In agreement with a previous study, most of these sites correspond to tRNA genes or genes that encode ribosomal proteins (RPGs). However, 147 of the SUMO peaks in our analysis are found at promoters of protein-coding genes that are not RPGs (non-RPGs), many of which are among the most highly expressed genes. By comparing our data with other ChIP-seq studies, we determined that non-RPG SUMO peaks are situated precisely where general transcription factors (GTFs) assemble, but not where RNA polymerase II (RNAPII) or other promoter-proximal proteins bind. In support of this, we determined that the large subunit of TFIIF is the major SUMO target among GTFs and propose that its sumoylation controls the dynamics of RNAPII gene association. Additionally, we found that exposing yeast to a brief heat shock significantly reduces the intensity of SUMO peaks at most genes of all classes, which likely reflects the vast transcriptional reprogramming that occurs in response to temperature stress.
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Project description:Rhes, a multifunctional striatal protein, regulates nuclear proteins and gene expression via SUMO-mediated mechnisms.
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Project description:Loss of nutrient supply elicits alterations of the SUMO proteome and sumoylation is crucial to various cellular processes including transcription. However, the physiological significance of sumoylation of transcriptional regulators is unclear. To begin clarifying this, we mapped the SUMO proteome under nitrogen-limiting conditions in Saccharomyces cerevisiae. Interestingly, several RNA polymerase III (RNAPIII) components are major SUMO targets under normal growth conditions, including Rpc53, Rpc82, and Ret1, and nutrient starvation results in rapid desumoylation of these proteins. These findings are supported by ChIP-seq experiments that show that SUMO is highly enriched at tDNA genes. Furthermore, RNA-seq experiments revealed that preventing sumoylation results in significantly decreased tRNA transcription. TORC1 inhibition resulted in the same effect, and our data indicate that the SUMO and TORC1 pathways are both required for robust tDNA expression. Importantly, tRNA transcription was strongly reduced in cells expressing a non-sumoylatable Rpc82-4KR mutant, which correlated with a misassembled RNAPIII transcriptional complex. Our data suggest that in addition to TORC1 activity, sumoylation of RNAPIII is key to reaching full translational capacity under optimal growth conditions.
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Project description:The post-translational modification of proteins by SUMO acts as a key gatekeeper of cell identity. In mouse embryonic fibroblast (MEFs), SUMO impedes reprogramming to pluripotency, while in embryonic stem cells (ESCs), it represses the emergence of totipotent-like cells, suggesting that SUMO targets distinct sets of substrates to preserve the somatic and pluripotent states. Using MS-based proteomics, we show here that the composition of the endogenous SUMOylomes differs dramatically between MEFs and ESCs. In MEFs, SUMOylated proteins organize in a rather diffuse functional network enriched in nuclear factors with general cellular functions. In contrast, in ESCs, SUMOylated proteins form a tightly interconnected network mainly composed of repressive chromatin complexes. We also characterized several SUMOylated pluripotency factors and show that SUMO modification of Dppa2 and Dppa4 hampers their ability to induce a totipotent-like state. Altogether, we propose that rewiring the repertoire of SUMO target networks is a major driver of cell fate transition during embryonic development.
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Project description:Transient brain ischemia massively activates global SUMOylation. A large fraction of SUMO targets are nuclear proteins involved in gene expression. However, gene expression profile modulated by ischemia-induced SUMOylation has not been studied. Using a SUMO knockdown (SUMO-KD) mouse model and microarray technique, we investigated how SUMOylation modulated gene expression after brain ischemia. Wild-type and SUMO-KD mice were subjected to transient forebrain ischemia or sham surgery. The hippocampal CA1 subfield samples collected at 3 hours reperfusion were analyzed using Affymetrix microarrays.
2016-08-01 | E-GEOD-80681 | biostudies-arrayexpress
Project description:The cellular protein quality control machinery is important for preventing protein misfolding and aggregation. Declining protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how neuronal proteostasis capacity changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc-EGFP), a conformationally unstable protein that requires chaperones for proper folding, and that reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked reaction of the Fluc-EGFP sensor in a mouse model of tauopathy, but not in mouse models of Huntington's disease. Mechanistic investigations in primary neuronal cultures demonstrate that different types of protein aggregates have distinct effects on the cellular protein quality control. Thus, Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.
| S-SCDT-EMBOJ-2020-107260 | biostudies-other
Project description:Huntingtons disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat mutation in the Huntingtin (HTT) gene. The mutation impacts neuronal protein homeostasis and cortical/striatal circuitry. SUMOylation, a post translational modification with broad cellular effects, directly modifies the Huntingtin protein (HTT), along with other key neuronal and synaptic proteins. Here we investigated proteome wide changes in striatal protein SUMOylation/protein SUMO interactions in the context of HD using R6/2 transgenic and non-transgenic (NT) control mice by performing SUMO protein enrichment from tissue followed by mass spectrometry. Significant changes in enrichment of known and previously unknown SUMOylated or SUMO interacting proteins were observed including those involved in presynaptic function and cytomatrix at the active zone scaffolding, cytoskeleton organization, and glutamatergic signaling. A network based approach identified altered pathways in HD tissue to include clathrin mediated endocytosis signaling, synaptogenesis signaling, synaptic long term potentiation, and SNARE signaling. Furthermore, the metabotropic glutamate receptor 7 (mGluR7), a key player in glutamatergic signaling, a core signaling pathway disrupted in HD was SUMO enriched and we show SUMO modification is enhanced by the E3 SUMO ligase Protein Inhibitor of Activated STAT1 (PIAS1). To evaluate functional measures of neuronal activity in HD cells in vitro we utilized primary neuronal cultures from R6/2 and NT mice and evaluated how modulation of SUMOylation via reduction of PIAS1 may impact specific readouts. A receptor internalization assay showed decreased mGluR7 internalization in R6/2 neurons compared to NT, and siRNA mediated knockdown of PIAS1 prevented this HD phenotype. In addition, microelectrode array analysis on primary neuron cultures indicated early timepoint hyperactivity in HD cells, while later timepoints demonstrated deficits in several measurements of neuronal activity within cortical neurons. HD phenotypes were rescued at select timepoints following knockdown of PIAS1. Taken together our results provide a mouse brain SUMO ome resource and show that significant alterations occur within the post-translational landscape and SUMO protein interactions for synaptic proteins in HD.
2023-10-25 | MSV000093185 | MassIVE
Project description:Transcription factors represent one of the largest groups of proteins regulated by SUMO, and their modification has generally been correlated with transcriptional repression. However, as most of the studies focus on specific sumoylated transcriptional regulators, the distribution and global role of SUMO on chromatin in relation to transcription regulation remain largely unknown. To investigate this role, we determined the occupancy of SUMO machinery proteins on chromatin by ChIP coupled to sequencing in human primary cells. Examination of 3 histone modifications, Polymerase II, SUMO1, SUMO2, Ubc9 and PIASy in proliferative and Ras-induced senescent fibroblasts.
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Project description:Transient brain ischemia massively activates global SUMOylation. A large fraction of SUMO targets are nuclear proteins involved in gene expression. However, gene expression profile modulated by ischemia-induced SUMOylation has not been studied. Using a SUMO knockdown (SUMO-KD) mouse model and microarray technique, we investigated how SUMOylation modulated gene expression after brain ischemia.
2016-08-01 | GSE80681 | GEO