Same agent, different messages: insight into transcriptional regulation by SIN3 isoforms

Chaubal, Ashlesha; Pile, Lori A.

doi:10.1186/s13072-018-0188-y

Cited by 42 publications

(44 citation statements)

References 78 publications

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“…SIN3A CpG 401 was deferentially methylated between non-responders (I NR1–11) and responders (I R1–19) ( p *, 0.024), with the non-responders exhibiting higher methylation rates across the entire CpG DNA sequence (data not shown). Since it is not a tissue-specific factor [ 32 ], the statistically significant differentiation of SIN3A methylation with a consequent differential expression of its protein product within PBMCs was not an unexpected result.…”

Section: Resultsmentioning

confidence: 99%

“…The methylation profile of all CpG islands gave significant results only when the research focused on well-characterized single erythroid colonies (BFU-Es), with the unique exception of the SIN3A CpG 401, which is not an erythroid tissue-specific factor. The SIN3A protein consists of multiple protein interaction domains and contacts a variety of binding partners to perform its biological function, whereas it is considered to co-operate with histone-modifying complexes exhibiting a global transcription regulatory property [ 32 ]. Hence, SIN3A was differentially methylated ( p *, 0.024) between the in vivo samples (PBMCs) of HU non-responders and HU responders.…”

Section: Discussionmentioning

confidence: 99%

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Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea

et al. 2018

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BackgroundWe aimed to clarify the emerging epigenetic landscape in a group of genes classified as “modifier genes” of the β-type globin genes (HBB cluster), known to operate in trans to accomplish the two natural developmental switches in globin expression, from embryonic to fetal during the first trimester of conception and from fetal to adult around the time of birth. The epigenetic alterations were determined in adult sickle cell anemia (SCA) homozygotes and SCA/β-thalassemia compound heterozygotes of Greek origin, who are under hydroxyurea (HU) treatment. Patients were distinguished in HU responders and HU non-responders (those not benefited from the HU) and both, and in vivo and in vitro approaches were implemented.ResultsWe examined the CpG islands’ DNA methylation profile of BCL11A, KLF1, MYB, MAP3K5, SIN3A, ZBTB7A, and GATA2, along with γ-globin and LRF/ZBTB7A expression levels. In vitro treatment of hematopoietic stem cells (HSCs) with HU induced a significant DNA hypomethylation pattern in ZBTB7A (p*, 0.04) and GATA2 (p*, 0.03) CpGs exclusively in the HU non-responders. Also, this group of patients exhibited significantly elevated baseline methylation patterns in ZBTB7A, before the HU treatment, compared to HU responders (p*, 0.019) and to control group of healthy individuals (p*, 0.021), which resembles a potential epigenetic barrier for the γ-globin expression. γ-Globin expression in vitro matched with detected HbF levels during patients’ monitoring tests (in vivo) under HU treatment, implying a good reproducibility of the in vitro HU epigenetic effect. LRF/ZBTB7A expression was elevated only in the HU non-responders under the influence of HU.ConclusionsThis is one of the very first pharmacoepigenomic studies indicating that the hypomethylation of ZBTB7A during HU treatment enhances the LRF expression, which by its turn suppresses the HbF resumption in the HU non-responders. Its role as an epigenetic regulator of hemoglobin switching is also supported by the wide distribution of ZBTB7A-binding sites within the 5′ CpG sequences of all studied human HBB cluster “modifier genes.” Also, the baseline methylation level of selective CpGs in ZBTB7A and GATA2 could be an indicator of the negative HU response among the β-type hemoglobinopathy patients.Electronic supplementary materialThe online version of this article (10.1186/s40246-018-0177-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea

et al. 2018

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“…In other organisms, Sin3 proteins are found in multiple complexes of heterogeneous composition (Chaubal and Pile 2018). At least two general types of SIN3 complex exist, which contain SAP30 and SDS3 homologs, or like Rpd3S, Rco1/Pf1 and Eaf3/MRG15 homologs.…”

Section: Discussionmentioning

confidence: 99%

“…A prevailing view is that the regulatory functions of SET1/COMPASS and Rpd3/Sin3 complexes are context dependent, but their mechanisms are not well understood (Chaubal and Pile, 2018;Howe et al, 2017). Given the biochemical activities of complex components, it is plausible that co-occupancy alters gene expression through changes in acetylation and methylation dynamics.…”

Section: Discussionmentioning

confidence: 99%

Physical and functional interaction between SET1/COMPASS complex component CFP-1 and a Sin3 HDAC complex

Beurton

Stempor

Caron

et al. 2018

Preprint

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The CFP1 CXXC zinc finger protein targets the SET1/COMPASS complex to non-methylated CpG rich promoters to implement tri-methylation of histone H3 Ly4 (H3K4me3). Although H3K4me3 is widely associated with gene expression, the effects of CFP1 loss depend on chromatin context, so it is important to understand the relationship between CFP1 and other chromatin factors. Using a proteomics approach, we identified an unexpected link between C. elegans CFP-1 and a Rpd3/Sin3 histone deacetylase complex. We find that mutants of CFP-1, SIN-3, and the catalytic subunit SET-2/SET1 have similar phenotypes and misregulate common genes. CFP-1 directly binds SIN-3 through a region including the conserved PAH1 domain and recruits SIN-3 and the HDA-1/HDAC subunit to H3K4me3 enriched promoters. Our results reveal a novel role for CFP-1 in mediating interaction between SET1/COMPASS and a Sin3 HDAC complex at promoters and uncover coordinate regulation of gene expression by chromatin complexes having distinct activities.

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“…These complexes include the nucleosome remodeling (NuRD) complex, corepressor for REST (CoREST) and the SIN3 complex, named for the scaffolding factor SIN3 6 . To add to the complexity, multiple distinct SIN3 complexes are present in a single organism 7 . These SIN3 HDAC complexes vary in subunit isoform specificity and accessory factor composition.…”

Section: Introductionmentioning

confidence: 99%

Systematic Analysis of SIN3 Histone Modifying Complex Components During Development

Barnes

Laity

Pilecki

et al. 2018

Sci Rep

Self Cite

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Establishment and maintenance of histone acetylation levels are critical for metazoan development and viability. Disruption of the balance between acetylation and deacetylation by treatment with chemical histone deacetylase (HDAC) inhibitors results in loss of cell proliferation, differentiation and/or apoptosis. Histone deacetylation by the SIN3 complex is essential in Drosophila and mice, as loss of the scaffolding factor SIN3 or the associated HDAC results in lethality. The objective of this study is to elucidate contributions of SIN3 complex components to these essential processes. We used the Drosophila model organism to carry out a systematic functional analysis of the SIN3 complex. We find that SIN3 associated proteins are essential for viability and cell proliferation during development. Additionally, tissue specific reduction of SIN3 complex components results in abnormal wing development. Interestingly, while knockdown of each factor resulted in similar phenotypes, their individual effects on recruitment of SIN3 to polytene chromosomes are distinct. Reduction of some factors leads to large changes in the morphology of the chromosome and/or greatly reduced SIN3 binding. These findings suggest that while individual SIN3 complex components work through distinct molecular mechanisms, they each make a substantial contribution to the overall function of this highly conserved histone deacetylase complex.

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Same agent, different messages: insight into transcriptional regulation by SIN3 isoforms

Cited by 42 publications

References 78 publications

Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea

Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea

Physical and functional interaction between SET1/COMPASS complex component CFP-1 and a Sin3 HDAC complex

Systematic Analysis of SIN3 Histone Modifying Complex Components During Development

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