Tet2 regulates Sin3a recruitment at active enhancers in embryonic stem cells

Flores, Julio C.; Dawlaty, Meelad M.

doi:10.1016/j.isci.2023.107170

Cited by 6 publications

(20 citation statements)

References 44 publications

(121 reference statements)

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“…These proteins have previously been shown to regulate gene transcription (12, 16, 28, 29). The observation of OGT with SAP25 is also consistent with several investigations that suggest that Sin3 complex, SAP25, OGT, and TET family proteins (TET1, TET2, and TET3) collaborate in regulating transcription (12, 14, 16, 30). .…”

Section: Resultssupporting

confidence: 91%

“…RNASeq analysis revealed that SAP25 was not expressed in the HEK293 cells we used for these affinity purifications (15). Intriguingly, the O-GlcNAc transferase OGT and TET1/2/3 DNA methylases, which are known to be associated with Sin3/HDAC (12–14), were also never detected from these various purifications from Flp-In™-293 cells, except in the Halo-SAP25 dataset. Therefore, SAP25 appears to be necessary for the recruitment of these enzymatic complexes to Sin3/HDAC.…”

Section: Discussionmentioning

confidence: 99%

“…While SIN3/HDACSin3/HDAC complexes mainly regulate gene transcription (12), several by deacetylating histone tails and altering the chromatin environment, components of the Sin3/HDAC complex interact with proteins carrying various enzymatic activities (11, 13, 14). Specifically, SIN3A has been linked to OGT, an O-linked N-acetylglucosamine transferase (12) and the TET DNA demethylases (13, 14).…”

Section: Introductionmentioning

confidence: 99%

“…More recently, we showed that human SAP25 captured complexes containing the Sin3 subunits SUDS3 and SAP30 (15). SAP25 has also been associated with various additional components of epigenetic-modifying complexes, such as OGT and TET2(11, 14, 16), with an L254F-OGT variant upregulating SAP25 in X-linked intellectual disability (17). Furthermore, Tet2 purified complexes were found to contain both OGT and Sin3 complex components SAP25, SIN3A, and SAP30 (14).…”

Section: Introductionmentioning

confidence: 99%

“…SAP25 has also been associated with various additional components of epigenetic-modifying complexes, such as OGT and TET2(11, 14, 16), with an L254F-OGT variant upregulating SAP25 in X-linked intellectual disability (17). Furthermore, Tet2 purified complexes were found to contain both OGT and Sin3 complex components SAP25, SIN3A, and SAP30 (14). In addition, John and coworkers recently proposed that IFIT1 regulates gene expression programs of the immune response by coordinating the removal of Sin3 repressor complexes containing SAP25from the IFNB1, IRF7, and IRF8 promoters (18).…”

Section: Introductionmentioning

confidence: 99%

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Distinct regions within SAP25 recruit O-linked glycosylation, DNA demethylation, and ubiquitin ligase and hydrolase activities to the Sin3/HDAC complex

Goswami,

Banks,

Thornton

et al. 2024

Preprint

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Epigenetic control of gene expression is crucial for maintaining gene regulation. Sin3 is an evolutionarily conserved repressor protein complex mainly associated with histone deacetylase (HDAC) activity. A large number of proteins are part of Sin3/HDAC complexes, and the function of most of these members remains poorly understood. SAP25, a previously identified Sin3A associated protein of 25 kDa, has been proposed to participate in regulating gene expression programs involved in the immune response but the exact mechanism of this regulation is unclear. SAP25 is not expressed in HEK293 cells, which hence serve as a natural knockout system to decipher the molecular functions uniquely carried out by this Sin3/HDAC subunit. Using molecular, proteomic, protein engineering, and interaction network approaches, we show that SAP25 interacts with distinct enzymatic and regulatory protein complexes in addition to Sin3/HDAC. While the O-GlcNAc transferase (OGT) and the TET1 /TET2/TET3 methylcytosine dioxygenases have been previously linked to Sin3/HDAC, in HEK293 cells, these interactions were only observed in the affinity purification in which an exogenously expressed SAP25 was the bait. Additional proteins uniquely recovered from the Halo-SAP25 pull-downs included the SCF E3 ubiquitin ligase complex SKP1/FBXO3/CUL1 and the ubiquitin carboxyl-terminal hydrolase 11 (USP11), which have not been previously associated with Sin3/HDAC. Finally, we use mutational analysis to demonstrate that distinct regions of SAP25 participate in its interaction with USP11, OGT/TETs, and SCF(FBXO3).) These results suggest that SAP25 may function as an adaptor protein to coordinate the assembly of different enzymatic complexes to control Sin3/HDAC-mediated gene expression.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Distinct regions within SAP25 recruit O-linked glycosylation, DNA demethylation, and ubiquitin ligase and hydrolase activities to the Sin3/HDAC complex

Goswami,

Banks,

Thornton

et al. 2024

Preprint

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Deciphering the TET3 interactome in primary thymic developing T cells

Theofilatos,

Ho,

Waitt

et al. 2024

iScience

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Catalytic-dependent and -independent roles of TET3 in the regulation of specific genetic programs during neuroectoderm specification

Ketchum,

Suzuki,

Dawlaty

2024

Commun Biol

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The ten-eleven-translocation family of proteins (TET1/2/3) are epigenetic regulators of gene expression. They regulate genes by promoting DNA demethylation (i.e., catalytic activity) and by partnering with regulatory proteins (i.e., non-catalytic functions). Unlike Tet1 and Tet2, Tet3 is not expressed in mouse embryonic stem cells (ESCs) but is induced upon ESC differentiation. However, the significance of its dual roles in lineage specification is less defined. By generating TET3 catalytic-mutant (Tet3m/m) and knockout (Tet3–/–) mouse ESCs and differentiating them to neuroectoderm (NE), we identify distinct catalytic-dependent and independent roles of TET3 in NE specification. We find that the catalytic activity of TET3 is important for activation of neural genes while its non-catalytic functions are involved in suppressing mesodermal programs. Interestingly, the vast majority of differentially methylated regions (DMRs) in Tet3m/m and Tet3–/– NE cells are hypomethylated. The hypo-DMRs are associated to aberrantly upregulated genes while the hyper-DMRs are linked to downregulated neural genes. We find the maintenance methyltransferase Dnmt1 as a direct target of TET3, which is downregulated in TET3-deficient NE cells and may contribute to the increased DNA hypomethylation. Our findings establish that the catalytic-dependent and -independent roles of TET3 have distinct contributions to NE specification with potential implications in development.

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Tet2 regulates Sin3a recruitment at active enhancers in embryonic stem cells

Cited by 6 publications

References 44 publications

Distinct regions within SAP25 recruit O-linked glycosylation, DNA demethylation, and ubiquitin ligase and hydrolase activities to the Sin3/HDAC complex

Distinct regions within SAP25 recruit O-linked glycosylation, DNA demethylation, and ubiquitin ligase and hydrolase activities to the Sin3/HDAC complex

Deciphering the TET3 interactome in primary thymic developing T cells

Catalytic-dependent and -independent roles of TET3 in the regulation of specific genetic programs during neuroectoderm specification

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