Class I Lysine Deacetylases Facilitate Glucocorticoid-induced Transcription

Kadiyala, Vineela; Patrick, Nina M.; Mathieu, Wana; Jaime-Frias, Rosa; Pookhao, Naruekamol; An, Lingling; Smith, Catharine L.

doi:10.1074/jbc.m113.505115

Cited by 23 publications

(20 citation statements)

References 45 publications

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“…On the one hand, the inhibitory effect does not appear to be due to steric hindrance because FKBP alone or fusions to other proteins of comparable size are inactive (data not shown). Furthermore, although our data are consistent with the established role of HDACl as a component of corepressor complexes, recent data based on the functional effects of HDAC1 knockdown have been interpreted as HDAC1 playing a positive role in GR transactivation (38). Whether this reflects indirect effects of HDAC1, or more complex interactions as has been suggested recently (39), remains to be determined.…”

Section: Discussionsupporting

confidence: 68%

Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor

Mapp¹,

Sturlis²,

Carolan³

et al. 2015

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Section: Discussionsupporting

confidence: 68%

Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor

Mapp¹,

Sturlis²,

Carolan³

et al. 2015

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“…Western blotting conditions for KDACs are described in our previous study [32]. For analysis of SRC proteins, cellular proteins were separated by SDS-PAGE and transferred onto a nitrocellulose membrane (Biorad) at 400 mA for 4 h. Membranes were blocked with 2% non-fat dry milk for 1 h, followed by exposure to primary antibodies at 4°C overnight.…”

Section: Methodsmentioning

confidence: 99%

“…After drug treatment cells were fixed with 1% formaldehyde at room temperature for 10 min and neutralized using 0.125 M glycine. Fixed cells were harvested and sonicated as described previously [32]. Five percent of the sonicated chromatin was removed for use as input.…”

Section: Methodsmentioning

confidence: 99%

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Class I lysine deacetylases promote glucocorticoid-induced transcriptional repression through functional interaction with LSD1

Patrick

Griggs

Icenogle

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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Small molecule inhibitors of lysine deacetylases (KDACs) are approved for clinical use in treatment of several diseases. Nuclear receptors, such as the glucocorticoid receptor (GR) use lysine acetyltransferases (KATs or HATs) and KDACs to regulate transcription through acetylation and deacetylation of protein targets such as histones. Previously we have shown that KDAC1 activity facilitates GR-activated transcription at about half of all cellular target genes. In the current study we examine the role of Class I KDACs in glucocorticoid-mediated repression of gene expression. Inhibition of KDACs through two structurally distinct Class I-selective inhibitors prevented dexamethasone (Dex)-mediated transcriptional repression in a gene-selective fashion. In addition, KDAC activity is also necessary to maintain repression. Steroid receptor coactivator 2 (SRC2), which is known to play a vital role in GR-mediated repression of pro-inflammatory genes, was found to be dispensable for repression of glucocorticoid target genes sensitive to KDAC inhibition. At the promoters of these genes, KDAC inhibition did not result in altered nucleosome occupancy or histone H3 acetylation. Surprisingly, KDAC inhibition rapidly induced a significant decrease in H3K4Me2 at promoter nucleosomes with no corresponding change in H3K4Me3, suggesting the activation of the lysine demethylase, LSD1/KDM1A. Depletion of LSD1 expression via siRNA restored Dex-mediated repression in the presence of KDAC inhibitors, suggesting that LSD1 activation at these gene promoters is incompatible with transcriptional repression. Treatment with KDAC inhibitors does not alter cellular levels of LSD1 or its association with Dex-repressed gene promoters. Therefore, we conclude that Class I KDACs facilitate Dex-induced transcriptional repression by suppressing LSD1 complex activity at selected target gene promoters. Rather than facilitating repression of transcription, LSD1 opposes it in these gene contexts.

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“…Genomic studies have detected HDACs primarily at active genes (11, 41) and transcriptome analysis of cells depleted of specific HDACs reveals both increases and decreases in expression (18, 42). The mechanism by which HDACs stimulate transcription is largely unknown.…”

Section: Discussionmentioning

confidence: 99%

RNAi screen in Drosophila larvae identifies histone deacetylase 3 as a positive regulator of the hsp70 heat shock gene expression during heat shock

Achary

Campbell

et al. 2014

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Transcription regulation of the Drosophila hsp70 gene is a complex process that involves regulation of multiple steps including establishment of paused Pol II and release of Pol II into elongation upon heat shock activation. While the major players involved in regulation of gene expression have been studied in detail, additional factors involved in this process continue to be discovered. To identify factors involved in hsp70 expression, we developed a screen that capitalizes on a visual assessment of heat shock activation using a hsp70-beta galactosidase reporter and publicly available RNAi fly lines to deplete candidate proteins. We validated the screen by showing that depletion of HSF, CycT, Cdk9, Nurf 301, or ELL prevented full induction of hsp70 by heat shock. Our screen also identified the histone deacetylase HDAC3 and its associated protein SMRTER as positive regulators of hsp70 activation. Additionally we show that HDAC3 and SMRTER contribute to hsp70 gene expression at a step subsequent to HSF-mediated activation and release of the paused Pol II that resides at the promoter prior to heat shock induction.

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Class I Lysine Deacetylases Facilitate Glucocorticoid-induced Transcription

Cited by 23 publications

References 45 publications

Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor

Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor

Class I lysine deacetylases promote glucocorticoid-induced transcriptional repression through functional interaction with LSD1

RNAi screen in Drosophila larvae identifies histone deacetylase 3 as a positive regulator of the hsp70 heat shock gene expression during heat shock

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