Soft repression: Subtle transcriptional regulation with global impact

Mitra, Anindita; Raicu, Ana‐Maria; Hickey, Stephanie L.; Pile, Lori A.; Arnosti, David N.

doi:10.1002/bies.202000231

Cited by 15 publications

(19 citation statements)

References 72 publications

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“…Additionally, we expected genes to have higher enrichment of H3K4me2 and H3K4me3 when compared to H3K4me1 levels. Our reasoning is that both of these marks are associated with actively expressed genes (Bernstein et al, 2005), and SIN3 has been shown to fine-tune the expression of expressed genes (Mitra et al, 2021). We downloaded H3K4 methylation data from NCBI GEO (Fig.…”

Section: Resultsmentioning

confidence: 99%

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SIN3 gene regulatory activity is linked to RNA polymerase II pausing

Soukar

Mitra

Pile

2023

Preprint

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The chromatin environment has a significant impact on gene expression. Chromatin structure is highly regulated by histone modifications and RNA polymerase II binding dynamics. The SIN3 histone modifying complex regulates the chromatin environment leading to changes in gene expression. In Drosophila melanogaster, the Sin3A gene is alternatively spliced to produce different protein isoforms, two of which include SIN3 220 and SIN3 187. Both SIN3 isoforms are scaffolding proteins that interact with several other factors to regulate the chromatin landscape. The mechanism through which the SIN3 isoforms regulate chromatin is not well understood. Here, we analyze publicly available data sets to allow us to ask specific questions on how SIN3 isoforms regulate chromatin and gene activity. We determined that genes repressed by the SIN3 isoforms exhibited enrichment in histone H3K4me2 and H3K4me3 near the transcription start site. We observed an increase in the amount of paused RNA polymerase II on the promoter of genes repressed by the isoforms as compared to genes that require SIN3 for maximum activation. Furthermore, we analyzed a subset of genes regulated by SIN3 187 that suggest a mechanism in which SIN3 187 might exhibit hard regulation as well as soft regulation. Data presented here expand our knowledge of how the SIN3 isoforms regulate the chromatin environment and RNA polymerase II binding dynamics.

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Section: Resultsmentioning

confidence: 99%

“…However, the way in which SIN3 isoforms repress or activate genes has not been fully elucidated. We recently explored a potential mechanism of gene regulation by SIN3 (Mitra et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

SIN3 gene regulatory activity is linked to RNA polymerase II pausing

Soukar

Mitra

Pile

2023

Preprint

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“…SIN3 controls gene expression through association with an HDAC as well as with distinct sets of accessory proteins, dependent on cell type (3). The SIN3 complex fine-tunes the expression of target genes rather than switching its targets on or off (4). While a few organisms, such as budding yeast, have a single SIN3 isoform, others express more than one isoform, including SIN3A and SIN3B, encoded by separate genes, in mammalian cells (5).…”

Section: Introductionmentioning

confidence: 99%

Isoforms of the transcriptional cofactor SIN3 differentially regulate genes necessary for energy metabolism and cell survival

Mitra

Soukar

et al. 2022

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The SIN3 scaffolding protein is a conserved transcriptional regulator known to fine-tune gene expression. In Drosophila, there are two major isoforms of SIN3, SIN3 220 and SIN3 187, which each assemble into multi-subunit histone modifying complexes. The isoforms have distinct developmental expression patterns and non-redundant functions. Gene regulatory network analyses indicate that both isoforms affect genes encoding proteins in pathways such as the cell cycle and cell morphogenesis. Interestingly, the SIN3 187 isoform uniquely regulates a subset of pathways including post-embryonic development, phosphate metabolism and apoptosis. Target genes in the phosphate metabolism pathway include nuclear-encoded mitochondrial genes coding for proteins responsible for oxidative phosphorylation, important for energy metabolism. Here, we investigate the role of SIN3 isoforms in regulating energy metabolism and cell survival genes. We find that ectopic expression of SIN3 187 represses expression of several nuclear-encoded mitochondrial genes affecting production of ATP and generation of reactive oxygen species (ROS). Forced expression of SIN3 187 also activates several pro-apoptotic and represses a few anti-apoptotic genes. In the SIN3 187 expressing cells, these gene expression patterns are accompanied with an increased sensitivity to paraquat-mediated oxidative stress. These findings indicate that SIN3 187 influences the regulation of mitochondrial function, apoptosis and oxidative stress response in ways that are dissimilar from SIN3 220. The data suggest that the distinct SIN3 histone modifying complexes are deployed in different cellular contexts to maintain cellular homeostasis.

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“…This includes histone deacetylase 1 (HDAC1) as well as distinct sets of accessory proteins, dependent on cell type (3). The SIN3 complex regulates and fine-tunes the expression of target genes rather than switching its targets on or off (4). While a few organisms, such as budding yeast, have a single SIN3 isoform, others express more than one isoform, including SIN3A and SIN3B, encoded by separate genes, in mammalian cells (5).…”

Section: Introductionmentioning

confidence: 99%