SAP18 Promotes Krüppel-dependent Transcriptional Repression by Enhancer-specific Histone Deacetylation

Matyash, Alexey; Singh, Navjot; Hanes, Steven D.; Urlaub, Henning; Jäckle, Herbert

doi:10.1074/jbc.m806163200

Cited by 9 publications

(9 citation statements)

References 66 publications

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“…Activation of hsp70 expression in dsap18 mutants under noninduced conditions is consistent with the previously reported role of SAP18 in transcriptional repression by association with the Sin3-HDAC co-repressor complex [3,5,6]. Our previous studies demonstrated the interaction between dSAP18 and GAGA [1], a transcription factor involved in hsp70 gene regulation [18], and it is tempting to speculate that this interaction could account for the tethering of dSAP18 to the hsp70 promoter region in basal conditions.…”

Section: Dsap18 Modulates Heat Shock Gene Expressionsupporting

confidence: 91%

“…SAP18 was initially identified in mammals as a component of the Sin3‐HDAC co‐repressor complex [3], suggesting a contribution to transcriptional regulation. Consistent with this hypothesis, SAP18 was found to modulate Gli‐mediated transcription, affecting hedgehog signaling in mammals [4], and to contribute to bicoid activity [5], kruppel‐dependent transcriptional repression [6] and homeotic gene regulation in Drosophila melanogaster [1,7]. SAP18, however, also seems to be involved in several other cellular functions.…”

Section: Introductionmentioning

confidence: 54%

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Drosophila melanogaster SAP18 protein is required for environmental stress responses

2010

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a b s t r a c t SAP18, a highly evolutionarily conserved protein, has been proposed to be involved in multiple cellular processes, from gene regulation to mRNA processing. To gain further insight into the role of SAP18, we performed genome-wide expression profiling of dsap18 mutant Drosophila melanogaster embryos and we found that dSAP18 is required for the expression of immune and stress related genes. We show that dSAP18 colocalizes with histone H3 phosphorylation, which has been implicated in the regulation of genes in response to signaling stimuli. dsap18 mutant larvae develop melanotic tumors after heat shock and the viability of dsap18 mutant flies is reduced after fungal infection or in high-salt medium. Altogether, our results indicate that dSAP18 is a key player in transcriptional responses to stress. Structured summary: dSAP18 and H3 colocalize: shown by fluorescence microscopy (view interaction)

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Section: Dsap18 Modulates Heat Shock Gene Expressionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 54%

Drosophila melanogaster SAP18 protein is required for environmental stress responses

2010

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“…It is also possible that SAP18 interacts with Drosophila SIN3 in a gene-specific manner or in response to a particular stimulus. Although SAP18 was isolated as part of a mammalian SIN3 complex (28), there is evidence to suggest that SAP18 is important for histone deacetylation at a specific subset of genes (53,54). In this way, it is possible that SAP18 is present in a subset of SIN3 complexes that were not abundant under our experimental conditions.…”

Section: Sin3 Isoforms Interact With a Common Set Of Proteins-mentioning

confidence: 78%

Drosophila SIN3 Isoforms Interact with Distinct Proteins and Have Unique Biological Functions

Spain

Caruso

Swaminathan

et al. 2010

Journal of Biological Chemistry

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The SIN3 corepressor serves as a scaffold for the assembly of histone deacetylase (HDAC) complexes. SIN3 and its associated HDAC have been shown to have critical roles in both development and the regulation of cell cycle progression. Although multiple SIN3 isoforms have been reported in simple to complex eukaryotic organisms, the mechanisms by which such isoforms regulate specific biological processes are still largely uncharacterized. To gain insight into how SIN3 isoform-specific function contributes to the growth and development of a metazoan organism, we have affinity-purified two SIN3 isoform-specific complexes, SIN3 187 and 220, from Drosophila S2 cells and embryos. We have identified a number of proteins common to the complexes, including the HDAC RPD3, as well as orthologs of several proteins known to have roles in regulating cell proliferation in other organisms. We additionally identified factors, including the histone demethylase little imaginal discs and histoneinteracting protein p55, that exhibited a preferential interaction with the largest SIN3 isoform. Our experiments indicate that the isoforms are associated with distinct HDAC activity and are recruited to unique and shared sites along polytene chromosome arms. Furthermore, although expression of SIN3 220 can substitute for genetic loss of other isoforms, expression of SIN3 187 does not support Drosophila viability. Together our findings suggest that SIN3 isoforms serve distinct roles in transcriptional regulation by partnering with different histone-modifying enzymes. Transcriptional regulation by SIN3 histone deacetylase (HDAC)2 complexes is essential for a number of important biological processes. For instance, SIN3 complexes are required for viability, as demonstrated by the finding that mutations in SIN3 result in embryonic lethality in both Drosophila and mouse (1-4). Furthermore, genome-wide localization and gene expression studies have mapped the SIN3 regulatory network to include nuclear genes involved in mitochondrial biogenesis and function (5), genes involved in DNA replication and repair (6), and genes involved in development (2, 5, 6). Additionally, functional studies in both Drosophila and mammalian systems have shown that SIN3 is an important factor in the regulation of cell cycle progression and exit (2, 3, 7-10). Together, these studies highlight the importance of SIN3 in both growth and development.The SIN3 corepressor serves as a scaffold for the assembly of HDAC complexes. These complexes are recruited to chromatin, where the catalytic subunit, RPD3 in yeast and Drosophila and HDAC1 and -2 in mammals, deacetylates histones to repress transcription (11,12). Compositionally similar SIN3 complexes from Saccharomyces cerevisiae, Schizosaccharomyces pombe, and mammals have been isolated and characterized, illustrating the conservation of SIN3 complex proteins among eukaryotes (11, 13). This similarity further suggests that the essential functions of these complexes may be conserved as well.In yeast, two distinct mechanisms of SI...

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“…ATF7IP/MCAF1, a member of the transcriptional regulation group, is required for placement of the repressive H3K9me3 modification in its role as a binding partner and cofactor for the histone modifying enzyme SETBD1/KMT1E, a factor also detected in the screen. SAP18 and HDAC1 are components of the Sin3 complex, 36 and knockdown of SAP18 was shown to activate silent cellular genes 37 . More unusual and unexpected roles for transcription factors in epigenetic gene silencing are possible.…”

Section: Discussionmentioning

confidence: 99%

Human factors and pathways essential for mediating epigenetic gene silencing

et al. 2014

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Cellular identity in both normal and disease processes is determined by programmed epigenetic activation or silencing of specific gene subsets. Here, we have used human cells harboring epigenetically silent GFP-reporter genes to perform a genome-wide siRNA knockdown screen for the identification of cellular factors that are required to maintain epigenetic gene silencing. This unbiased screen interrogated 21,121 genes, and we identified and validated a set of 128 protein factors. This set showed enrichment for functional categories, and protein-protein interactions. Among this set were known epigenetic silencing factors, factors with no previously identified role in epigenetic gene silencing, as well as unstudied factors. The set included non-nuclear factors, for example, components of the integrin-adhesome. A key finding was that the E1 and E2 enzymes of the small ubiquitin-like modifier (SUMO) pathway (SAE1, SAE2/UBA2, UBC9/UBE2I) are essential for maintenance of epigenetic silencing. This work provides the first genome-wide functional view of human factors that mediate epigenetic gene silencing. The screen output identifies novel epigenetic factors, networks, and mechanisms, and provides a set of candidate targets for epigenetic therapy and cellular reprogramming.

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SAP18 Promotes Krüppel-dependent Transcriptional Repression by Enhancer-specific Histone Deacetylation

Cited by 9 publications

References 66 publications

Drosophila melanogaster SAP18 protein is required for environmental stress responses

Drosophila melanogaster SAP18 protein is required for environmental stress responses

Drosophila SIN3 Isoforms Interact with Distinct Proteins and Have Unique Biological Functions

Human factors and pathways essential for mediating epigenetic gene silencing

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