Class I HDACs Share a Common Mechanism of Regulation by Inositol Phosphates

Millard, Christopher; Watson, Peter J.; Celardo, Ivana; Gordiyenko, Yuliya; Cowley, Shaun M.; Robinson, Carol V.; Fairall, Louise; Schwabe, John W. R.

doi:10.1016/j.molcel.2013.05.020

Cited by 333 publications

(433 citation statements)

References 36 publications

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“…A general model that embraces knowledge from other systems (19,20,22) is that certain IP metabolites may specifically bind to proteins that have roles in telomeric silencing and affect their interactions with other proteins and/or their functions, e.g., histone modification and chromatin remodeling. The ultimate consequence of the derepression is that the chromatin at multiple ESs is permissive for the elongation of transcription by Pol I through the VSG genes.…”

Section: Discussionmentioning

confidence: 99%

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Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes

Cestari

Stuart

2015

Proc. Natl. Acad. Sci. U.S.A.

143

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African trypanosomes evade clearance by host antibodies by periodically changing their variant surface glycoprotein (VSG) coat. They transcribe only one VSG gene at a time from 1 of about 20 telomeric expression sites (ESs). They undergo antigenic variation by switching transcription between telomeric ESs or by recombination of the VSG gene expressed. We show that the inositol phosphate (IP) pathway controls transcription of telomeric ESs and VSG antigenic switching in Trypanosoma brucei. Conditional knockdown of phosphatidylinositol 5-kinase (TbPIP5K) or phosphatidylinositol 5-phosphatase (TbPIP5-Pase) or overexpression of phospholipase C (TbPLC) derepresses numerous silent ESs in T. brucei bloodstream forms. The derepression is specific to telomeric ESs, and it coincides with an increase in the number of colocalizing telomeric and RNA polymerase I foci in the nucleus. Monoallelic VSG transcription resumes after reexpression of TbPIP5K; however, most of the resultant cells switched the VSG gene expressed. TbPIP5K, TbPLC, their substrates, and products localize to the plasma membrane, whereas TbPIP5Pase localizes to the nucleus proximal to telomeres. TbPIP5Pase associates with repressor/activator protein 1 (TbRAP1), and their telomeric silencing function is altered by TbPIP5K knockdown. These results show that specific steps in the IP pathway control ES transcription and antigenic switching in T. brucei by epigenetic regulation of telomere silencing.O nly one of the ∼20 telomeric expression sites (ESs) is transcribed at a time in Trypanosoma brucei in the mammalian infectious stage bloodstream (BF) or metacyclic forms (MFs), whereas no ES is transcribed in the insect stage procyclic forms (PFs) (1). Each ES contains 1 telomeric variant surface glycoprotein (VSG) gene, whose expression confers a distinct cellular antigenic type and up to 12 expression site-associated genes (ESAGs) whose functions are incompletely understood ( Fig. 1A) (2-4). The parasites evade immune clearance by periodically changing antigenic type by switching transcription between ESs or by ES recombination with the ∼2,500 non-ES VSG genes and pseudogenes (5, 6). ESs are transcribed by RNA polymerase I (Pol I), which initiates at the single promoter at all ESs but terminates within a few kilobases except at one fully transcribed ES (7,8).RNAi knockdown of expression of the nuclear protein TbRAP1 that interacts with the TTAGGG-binding factor (TbTRF) or of the nuclear lamina protein 1 (TbNUP1) or deletion of the histonelysine N-methyltransferase DOT1B (TbDOT1B) alleles each results in transcription of silent ESs (9-11). Similarly, RNAi knockdown of the transcription facilitating histone chaperone suppressor of ty 16 (TbSPT16) or the SWI2/SNF2-related chromatin-remodeling protein TbISWI or deletion of histone deacetylase sirtuin 2-related protein 1 (TbSIR2RP1) each increases transcription near the promoter but not the VSG gene of silent . These results indicate that the control of ES transcription involves telomeric silencing (15), which entails...

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Section: Discussionmentioning

confidence: 99%

“…Soluble IPs or lipid-conjugated phosphatidylinositols (PIs) occur in various cellular compartments, where they act as cofactors in the regulation of the functions or interactions of proteins (22,23). Knowing this, we explored the role of the IP pathway in the control of telomeric ESs transcription and VSG switching (see Tables S1 and S2 for gene IDs).…”

mentioning

confidence: 99%

Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes

Cestari

Stuart

2015

Proc. Natl. Acad. Sci. U.S.A.

143

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“…[69][70][71] CoREST proteins are integral subunits of chromatin modifying complexes that contribute to the generation of repressive chromatin. These conserved complexes combine histone demethylase and deacetylase activities and have been identified in Drosophila, 72 C. elegans 73,74 and mammals.…”

Section: The Corest Proteinmentioning

confidence: 99%

Chromatin regulation: How complex does it get?

Meier¹,

Brehm

2014

Epigenetics

100

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“…The recruitment and activity of HDAC1/2 within these multiprotein complexes was thought to be a constitutive process. However, it has recently been shown that the HDAC1/metastasis-associated 1 (MTA1) complex (of NuRD) is regulated by a molecule of inositol tetraphosphate [Ins(1,4,5,6)P 4 ] (IP 4 ), which regulates its enzymatic activity, presumably in response to external signaling pathways (5). Because deacetylation of histone tails results in the tightening of nucleosomal arrays (6), the physiological roles of HDAC1/2 have mostly been defined within the context of transcriptional repression.…”

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confidence: 99%

Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells

Jamaladdin

Kelly

O’Regan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

140

125

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Histone deacetylases 1 and 2 (HDAC1/2) form the core catalytic components of corepressor complexes that modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an ES cell line in which Hdac1 and Hdac2 can be inactivated simultaneously. Loss of HDAC1/2 resulted in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is dependent upon cell cycle progression, because differentiated, nonproliferating cells retain their viability. Furthermore, we observe increased mitotic defects, chromatin bridges, and micronuclei, suggesting HDAC1/2 are necessary for accurate chromosome segregation. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2-deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog, Esrrb, and Rex1. HDAC1/2 activity is regulated through binding of an inositol tetraphosphate molecule (IP 4 ) sandwiched between the HDAC and its cognate corepressor. This raises the important question of whether IP 4 regulates the activity of the complex in cells. By rescuing the viability of double-knockout cells, we demonstrate for the first time (to our knowledge) that mutations that abolish IP 4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have essential and pleiotropic roles in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors.

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Class I HDACs Share a Common Mechanism of Regulation by Inositol Phosphates

Cited by 333 publications

References 36 publications

Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes

Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes

Chromatin regulation: How complex does it get?

Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells

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