Identification of Genetic Suppressors of the Sin3A Knockdown Wing Phenotype

Swaminathan, Aishwarya; Barnes, Valerie L.; Fox, Stéphanie; Gammouh, Sarah; Pile, Lori A.

doi:10.1371/journal.pone.0049563

Cited by 6 publications

(10 citation statements)

References 119 publications

(150 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the earlier effort demonstrated that Sin3A activity is regulated through the Wnt/β-catenin signaling pathway in Drosophila development27. On this basis, we tested whether Wnt/β-catenin and Shh signaling pathways were involved in neuronal differentiation induced by Sin3A knockdown in pluripotent P19 cells.…”

Section: Resultsmentioning

confidence: 99%

Suppression of Sin3A activity promotes differentiation of pluripotent cells into functional neurons

Halder

Lee

Hyun

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Sin3 is a transcriptional corepressor for REST silencing machinery that represses multiple neuronal genes in non-neuronal cells. However, functions of Sin3 (Sin3A and Sin3B) in suppression of neuronal phenotypes are not well characterized. Herein we show that Sin3A knockdown impedes the repressive activity of REST and enhances differentiation of pluripotent P19 cells into electrophysiologically active neurons without inducing astrogenesis. It is also found that silencing Sin3B induces neurogenesis of P19 cells with a lower efficiency than Sin3A knockdown. The results suggest that Sin3A has a more profound effect on REST repressive machinery for silencing neuronal genes in P19 cells than Sin3B. Furthermore, we show that a peptide inhibitor of Sin3A-REST interactions promotes differentiation of P19 cells into functional neurons. Observations made in studies using genetic deletion and a synthetic inhibitor suggests that Sin3A plays an important role in the repression of neuronal genes by the REST regulatory mechanism.

show abstract

Section: Resultsmentioning

confidence: 99%

Suppression of Sin3A activity promotes differentiation of pluripotent cells into functional neurons

Halder

Lee

Hyun

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…RNAi screens performed in cultured cells revealed that SIN3 is a putative regulator of neural and cardiac development as well as an active player in ERK and JNK signaling [19, 20]. A recent genetic screen to identify suppressors of the Sin3A knockdown curved wing phenotype found that genes involved in multiple processes during development, including regulation of the cell cycle, Wnt signaling, metabolism and transcription, interacted with Sin3A [21]. …”

Section: Introductionmentioning

confidence: 99%

SIN3 is critical for stress resistance and modulates adult lifespan

Barnes

Bhat

Unnikrishnan

et al. 2014

Aging

Self Cite

View full text Add to dashboard Cite

Coordinate control of gene activity is critical for fitness and longevity of an organism. The SIN3 histone deacetylase (HDAC) complex functions as a transcriptional repressor of many genes. SIN3-regulated genes include those that encode proteins affecting multiple aspects of mitochondrial function, such as energy production and stress responsiveness, important for health maintenance. Here we used Drosophila melanogaster as a model organism to examine the role of SIN3 in the regulation of fitness and longevity. Adult flies with RNA interference (RNAi) induced knockdown expression of Sin3A have reduced climbing ability; an activity that likely requires fully functional mitochondria. Additionally, compared to wild type, adult Sin3A knockdown flies were more sensitive to oxidative stress. Interestingly, media supplementation with the antioxidant glutathione largely restored fly tolerance to oxidative stress. Although Sin3A knockdown flies exhibited decreased longevity compared to wild type, no significant changes in expression of many well-categorized aging genes were observed. We found, however, that Sin3A knockdown corresponded to a significant reduction in expression of genes encoding proteins involved in the de novo synthesis of glutathione. Taken together, the data support a model whereby SIN3 regulates a gene expression program required for proper mitochondrial function and effective stress response during adulthood.

show abstract

“…Because SIN3 is part of an HDAC complex, which contains both a histone deacetylase RPD3 and a histone demethylase dKDM5/LID (15,16), we asked whether the increase of both H3K9ac and H3K4me3 at the promoters of methionine metabolism genes in Sin3A knockdown cells is due to instability of the complex and degradation of RPD3 and dKDM5/LID following knockdown of Sin3A. Our published RNA-Seq data indicate that the expression of rpd3 and lid is not changed when SIN3 is decreased (16).…”

Section: Sin3 Regulates Expression Of Methionine Metabolic Genes and mentioning

confidence: 99%

“…In Drosophila and mammals, a histone demethylase is also part of a SIN3/RPD3 HDAC complex (14). We previously reported a genetic interaction between Drosophila Sin3A and the genes encoding the histone demethylases KDM2 and dKDM5/LID (15,16). These biochemical and genetic data suggest that the SIN3 complex may regulate histone methylation in addition to histone acetylation.…”

mentioning

confidence: 89%

“…For example, reduced methionine leads to decreased H3K4me3 in yeast and mammalian cells, at least in part by modulating SAM levels (7)(8)(9). Given that SIN3 may regulate histone methylation because of its biochemical or genetic association with the histone demethylases dKDM5/LID and KDM2 (15,16,29,30), we wanted to examine further the relationship between SIN3 and methionine metabolism in Drosophila.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The Transcriptional Corepressor SIN3 Directly Regulates Genes Involved in Methionine Catabolism and Affects Histone Methylation, Linking Epigenetics and Metabolism

Liu

Pile

2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Chromatin modification and cellular metabolism are tightly connected. Chromatin modifiers regulate the expression of genes involved in metabolism and, in turn, the levels of metabolites. The generated metabolites are utilized by chromatin modifiers to affect epigenetic modification. The mechanism for this cross-talk, however, remains incompletely understood. The corepressor SIN3 controls histone acetylation through association with the histone deacetylase RPD3. The SIN3 complex is known to regulate genes involved in a number of metabolic processes. Here, we find that Drosophila SIN3 binds to the promoter region of genes involved in methionine catabolism and that this binding affects histone modification, which in turn influences gene expression. Specifically, we observe that reduced expression of SIN3 leads to an increase in S-adenosylmethionine (SAM), which is the major cellular donor of methyl groups for protein modification. Additionally, Sin3A knockdown results in an increase in global histone H3K4me3 levels. Furthermore, decreased H3K4me3 caused by knockdown of either SAM synthetase (Sam-S) or the histone methyltransferase Set1 is restored to near normal levels when SIN3 is also reduced. Taken together, these results indicate that knockdown of Sin3A directly alters the expression of methionine metabolic genes to increase SAM, which in turn leads to an increase in global H3K4me3. Our study reveals that SIN3 is an important epigenetic regulator directly connecting methionine metabolism and histone modification.

show abstract

Identification of Genetic Suppressors of the Sin3A Knockdown Wing Phenotype

Cited by 6 publications

References 119 publications

Suppression of Sin3A activity promotes differentiation of pluripotent cells into functional neurons

Suppression of Sin3A activity promotes differentiation of pluripotent cells into functional neurons

SIN3 is critical for stress resistance and modulates adult lifespan

The Transcriptional Corepressor SIN3 Directly Regulates Genes Involved in Methionine Catabolism and Affects Histone Methylation, Linking Epigenetics and Metabolism

Contact Info

Product

Resources

About