Holocarboxylase synthetase synergizes with methyl CpG binding protein 2 and DNA methyltransferase 1 in the transcriptional repression of long-terminal repeats

Xue, Jing; Wijeratne, Subhashinee S.K.; Zempleni, Janos

doi:10.4161/epi.24449

Cited by 23 publications

(19 citation statements)

References 46 publications

(87 reference statements)

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“…The present study supports a model in which HLCS and biotin participate in the repression of genes at the epigenetic level through orchestrating the assembly of a multi-protein gene repression complex that integrates DNA methylation, histone H3 methylation and histone deacetylation events [20,21]. There is high confidence that the reported interactions are real, based on the following lines of reasoning.…”

Section: Discussionsupporting

confidence: 83%

“…HLCS was overexpressed using plasmid p3XFLAG-Myc-CMV-26-HLCS [20] and the efficacy of HLCS overexpression was assessed at the mRNA and protein levels. The abundance of mRNA coding for HLCS was approximately 49-fold greater in overexpression cells compared with the non-transfected controls and the increase in protein abundance was equally compelling (Figure 9A and insert).…”

Section: Resultsmentioning

confidence: 99%

“…were cultured in DMEM (Dulbecco’s modified Eagle’s medium; Thermo Scientific) containing 10% FBS, 1% l -glutamine, 1% penicillin/streptomycin and 0.1% sodium pyruvate. HLCS-overexpression cells were created by transfecting HEK-293 cells with the plasmid FLAG/Myc-HLCS using electroporation as described previously [20]. The expression of HLCS was assessed by Western blot analysis and qPCR (quantitative real-time PCR) as described previously using the PCR primer pair denoted ‘25’ given in Supplementary Table S1 (http://www.biochemj.org/bj/461/bj4610477add.htm) [7].…”

Section: Methodsmentioning

confidence: 99%

“…According to this model, HLCS is recruited to chromatin through physical interactions with the maintenance DNA methyltransferase DNMT1 (DNA methyltransferase 1) and the MeCP2 (methyl CpG-binding protein 2), [20], consistent with previous observations that erasure of DNA methylation marks impairs HLCS-dependent biotinylation events in chromatin [14]. Also according to this model, chromatin-bound HLCS recruits the eukaryotic histone H3 methyltransferase EHMT-1 (euchromatic histonelysine N -methyltransferase-1), which creates abundant H3K9me (Lys 9 -methylated histone H3) gene repression marks; the physical interaction between HLCS and EHMT-1 appears to be strengthened by HLCS-dependent biotinylation of Lys 161 in EHMT-1 [21].…”

Section: Introductionmentioning

confidence: 99%

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Holocarboxylase synthetase interacts physically with nuclear receptor co-repressor, histone deacetylase 1 and a novel splicing variant of histone deacetylase 1 to repress repeats

Liu

Zempleni

2014

Biochemical Journal

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HLCS (holocarboxylase synthetase) is a nuclear protein that catalyses the binding of biotin to distinct lysine residues in chromatin proteins. HLCS-dependent epigenetic marks are overrepresented in repressed genomic loci, particularly in repeats. Evidence is mounting that HLCS is a member of a multi-protein gene repression complex, which determines its localization in chromatin. In the present study we tested the hypothesis that HLCS interacts physically with N-CoR (nuclear receptor co-repressor) and HDAC1 (histone deacetylase 1), thereby contributing toward the removal of H3K9ac (Lys9-acetylated histone H3) gene activation marks and the repression of repeats. Physical interactions between HLCS and N-CoR, HDAC1 and a novel splicing variant of HDAC1 were confirmed by co-immunoprecipitation, limited proteolysis and split luciferase complementation assays. When HLCS was overexpressed, the abundance of H3K9ac marks decreased by 50% and 68% in LTRs (long terminal repeats) 15 and 22 respectively in HEK (human embryonic kidney)-293 cells compared with the controls. This loss of H3K9ac marks was linked with an 83% decrease in mRNA coding for LTRs. Similar patterns were seen in pericentromeric alpha satellite repeats in chromosomes 1 and 4. We conclude that interactions of HLCS with N-CoR and HDACs contribute towards the transcriptional repression of repeats, presumably increasing genome stability.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Holocarboxylase synthetase interacts physically with nuclear receptor co-repressor, histone deacetylase 1 and a novel splicing variant of histone deacetylase 1 to repress repeats

Liu

Zempleni

2014

Biochemical Journal

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“…This model posits that HLCS, which lacks a strong DNA‐binding motif, binds to chromatin by interacting with other chromatin proteins, thereby creating a multiprotein gene repression complex (Figure ). Unambiguous evidence suggests that HLCS interacts with the maintenance DNA methyltransferase DNMT1 (but not with the de novo methyltransferases DNMT3a and DNMT3b) and the methyl‐CpG‐binding protein MeCP2, which explains why the binding of HLCS to chromatin and subsequent creation of histone biotinylation marks depends on DNA methylation marks . HLCS also interacts physically with the euchromatic histone‐lysine methyltransferase EHMT1 .…”

Section: Novel Roles Of Hlcs In Chromatin and Epigeneticsmentioning

confidence: 99%

Novel roles of holocarboxylase synthetase in gene regulation and intermediary metabolism

et al. 2014

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The role of HLCS in catalyzing of covalent binding of biotin to the 5 human biotin dependent carboxylases is well established, as are the essential roles of these carboxylases in the metabolism of fatty acids, catabolism of leucine, and gluconeogenesis. Here we review recent discoveries regarding the roles of HLCS in assembling a multiprotein gene repression complex in chromatin. We also discuss emerging evidence suggesting that the number of biotinylated proteins is far larger than previously assumed, including members of the heat shock superfamily of proteins and proteins coded by the ENO1 gene. Evidence is presented linking biotinylation of heat shock proteins HSP60 and HSP72 with redox biology and immune function, respectively, and biotinylation of the two ENO1 gene products MBP-1 and ENO1 with tumor suppression and glycolysis, respectively.

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Rb silencing mediated by the down‐regulation of MeCP2 is involved in cell transformation induced by long‐term exposure to hydroquinone

Liu

Ling

et al. 2016

Molecular Carcinogenesis

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Hydroquinone (HQ), a metabolite of benzene, is a well-known human carcinogen; however, its molecular mechanisms of action remain unclear. MeCP2 has been traditionally described as a transcriptional repressor, though growing evidence indicates that it also activates gene expression. Here, we investigated whether some epigenetic machinery genes are aberrantly expressed as target tumor suppressor genes in HQ-transformed TK6 lymphoblastoid cells. Our results showed that treatment with 5-Aza-2'-deoxycytidine or trichostatin A enhanced the expression of Rb, resulting in cell arrest in G1-phase, and subsequently, an increase in apoptosis and a decrease in cell growth. Moreover, we hypothesised that Rb was silenced by the down-regulation of MeCP2 in HQ-transformed cells, resulting in the dynamic expression of Rb and epigenetic machinery proteins in HQ-transformed cells at different time points. The expression of Rb and MeCP2 in patients with B-cell non-Hodgkin's lymphoma (B-NHL) showed that positive staining for MeCP2 or Rb was significantly lower in B-NHL tumor tissues, and these changes were significantly and negatively correlated with the grade of B-NHL. The restoration of MeCP2 in HQ-transformed cells enhanced the expression of Rb, promoted cell apoptosis, and inhibited cell growth. The changes in the expression patterns of MeCP2 and Rb were inversely correlated with the degree of DNA methylation. A ChiP assay revealed that MeCP2 proteins were recruited to the Rb promoter with lower 5'-methylcytosine levels. In conclusion, we demonstrated that the down-regulation of MeCP2 silences Rb, a process involved in cell transformation resulting from long-term exposure to HQ. © 2016 Wiley Periodicals, Inc.

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Holocarboxylase synthetase synergizes with methyl CpG binding protein 2 and DNA methyltransferase 1 in the transcriptional repression of long-terminal repeats

Cited by 23 publications

References 46 publications

Holocarboxylase synthetase interacts physically with nuclear receptor co-repressor, histone deacetylase 1 and a novel splicing variant of histone deacetylase 1 to repress repeats

Holocarboxylase synthetase interacts physically with nuclear receptor co-repressor, histone deacetylase 1 and a novel splicing variant of histone deacetylase 1 to repress repeats

Novel roles of holocarboxylase synthetase in gene regulation and intermediary metabolism

Rb silencing mediated by the down‐regulation of MeCP2 is involved in cell transformation induced by long‐term exposure to hydroquinone

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