HDAC Stimulates Gene Expression Through BRD4 Availability in Response to IFN and in Interferonopathies

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2018 Nov 23

PMID 30463877

Citations 27

Authors

Isabelle J Marie

Hao-Ming Chang

David E Levy

Affiliations

Soon will be listed here.

Abstract

In contrast to the common role of histone deacetylases (HDACs) for gene repression, HDAC activity provides a required positive function for IFN-stimulated gene (ISG) expression. Here, we show that HDAC1/2 as components of the Sin3A complex are required for ISG transcriptional elongation but not for recruitment of RNA polymerase or transcriptional initiation. Transcriptional arrest by HDAC inhibition coincides with failure to recruit the epigenetic reader Brd4 and elongation factor P-TEFb due to sequestration of Brd4 on hyperacetylated chromatin. Brd4 availability is regulated by an equilibrium cycle between opposed acetyltransferase and deacetylase activities that maintains a steady-state pool of free Brd4 available for recruitment to inducible promoters. An ISG expression signature is a hallmark of interferonopathies and other autoimmune diseases. Combined inhibition of HDAC1/2 and Brd4 resolved the aberrant ISG expression detected in cells derived from patients with two inherited interferonopathies, ISG15 and USP18 deficiencies, defining a novel therapeutic approach to ISG-associated autoimmune diseases.

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References

Nilsson L, Green L, Muralidharan S, Demir D, Welin M, Bhadury J . Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins. Cancer Res. 2016; 76(8):2376-83. DOI: 10.1158/0008-5472.CAN-15-2721. View

Gottlicher M, Minucci S, Zhu P, Kramer O, SCHIMPF A, Giavara S . Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001; 20(24):6969-78. PMC: 125788. DOI: 10.1093/emboj/20.24.6969. View

Rasmussen T . Developmentally-poised chromatin of embryonic stem cells. Front Biosci. 2007; 13:1568-77. DOI: 10.2741/2781. View

Ramanathan Y, Rajpara S, Reza S, Lees E, Shuman S, Mathews M . Three RNA polymerase II carboxyl-terminal domain kinases display distinct substrate preferences. J Biol Chem. 2001; 276(14):10913-20. DOI: 10.1074/jbc.M010975200. View

Gomes N, Bjerke G, Llorente B, Szostek S, Emerson B, Espinosa J . Gene-specific requirement for P-TEFb activity and RNA polymerase II phosphorylation within the p53 transcriptional program. Genes Dev. 2006; 20(5):601-12. PMC: 1410802. DOI: 10.1101/gad.1398206. View

Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer S, Yuan C . Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. Nature. 2014; 517(7532):89-93. PMC: 4303590. DOI: 10.1038/nature13801. View

Hargreaves D, Horng T, Medzhitov R . Control of inducible gene expression by signal-dependent transcriptional elongation. Cell. 2009; 138(1):129-45. PMC: 2828818. DOI: 10.1016/j.cell.2009.05.047. View

Gill G, Pascal E, Tseng Z, Tjian R . A glutamine-rich hydrophobic patch in transcription factor Sp1 contacts the dTAFII110 component of the Drosophila TFIID complex and mediates transcriptional activation. Proc Natl Acad Sci U S A. 1994; 91(1):192-6. PMC: 42912. DOI: 10.1073/pnas.91.1.192. View

Darnell Jr J . Variety in the level of gene control in eukaryotic cells. Nature. 1982; 297(5865):365-71. DOI: 10.1038/297365a0. View

10.

Levy A, Noll M . Chromatin fine structure of active and repressed genes. Nature. 1981; 289(5794):198-203. DOI: 10.1038/289198a0. View

11.

Mulholland N, Soeth E, Smith C . Inhibition of MMTV transcription by HDAC inhibitors occurs independent of changes in chromatin remodeling and increased histone acetylation. Oncogene. 2003; 22(31):4807-18. DOI: 10.1038/sj.onc.1206722. View

12.

Sakamoto S, Potla R, Larner A . Histone deacetylase activity is required to recruit RNA polymerase II to the promoters of selected interferon-stimulated early response genes. J Biol Chem. 2004; 279(39):40362-7. DOI: 10.1074/jbc.M406400200. View

13.

Decker T, Lew D, Cheng Y, Levy D, Darnell Jr J . Interactions of alpha- and gamma-interferon in the transcriptional regulation of the gene encoding a guanylate-binding protein. EMBO J. 1989; 8(7):2009-14. PMC: 401078. DOI: 10.1002/j.1460-2075.1989.tb03608.x. View

14.

Hu X, Lu X, Liu R, Ai N, Cao Z, Li Y . Histone cross-talk connects protein phosphatase 1α (PP1α) and histone deacetylase (HDAC) pathways to regulate the functional transition of bromodomain-containing 4 (BRD4) for inducible gene expression. J Biol Chem. 2014; 289(33):23154-23167. PMC: 4132813. DOI: 10.1074/jbc.M114.570812. View

15.

Wada T, Takagi T, Yamaguchi Y, Ferdous A, Imai T, Hirose S . DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev. 1998; 12(3):343-56. PMC: 316480. DOI: 10.1101/gad.12.3.343. View

16.

Veals S, Schindler C, Leonard D, Fu X, Aebersold R, Darnell Jr J . Subunit of an alpha-interferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins. Mol Cell Biol. 1992; 12(8):3315-24. PMC: 364572. DOI: 10.1128/mcb.12.8.3315-3324.1992. View

17.

Diamant G, Amir-Zilberstein L, Yamaguchi Y, Handa H, Dikstein R . DSIF restricts NF-κB signaling by coordinating elongation with mRNA processing of negative feedback genes. Cell Rep. 2012; 2(4):722-31. DOI: 10.1016/j.celrep.2012.08.041. View

18.

Rodero M, Crow Y . Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J Exp Med. 2016; 213(12):2527-2538. PMC: 5110029. DOI: 10.1084/jem.20161596. View

19.

Balciunaite E, Spektor A, Lents N, Cam H, Te Riele H, Scime A . Pocket protein complexes are recruited to distinct targets in quiescent and proliferating cells. Mol Cell Biol. 2005; 25(18):8166-78. PMC: 1234327. DOI: 10.1128/MCB.25.18.8166-8178.2005. View

20.

Kuleshov M, Jones M, Rouillard A, Fernandez N, Duan Q, Wang Z . Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016; 44(W1):W90-7. PMC: 4987924. DOI: 10.1093/nar/gkw377. View