Epigenome-Modifying Tools in Asthma

Figures & data

Table 1.  List of epigenetic modifying tool compounds.

Epigenetic mark	Target	Tool compound	Affected process
Histone acetylation	Pan histone deacetylase inhibitors	Trichostatin A	Cancer treatment reduced IL-17 and T helper cell number, reduced TGF-β in mouse BAL [62,63]
		Vorinostat	Cancer treatment and graft vs host disease [63]
	BET domain mimics – block readers of acetylation	JQ1	Prevent cell cycle progression and investigated as an anticancer treatment [64,65]
Histone methylation:
– Histone 3 lysine 4 (H3K4)	SETD7	PFI-2	H3K4 is linked to activation of inflammatory responses [26,66]
– Histone 3 lysine 9 (H3K9)	G9a (H3K9 methyltransferase)	UNC0642	Macrophages and dendritic cells of asthmatics undergoing allergen exposure may benefit from the inhibition of H3K9 methyltransferases, to prevent activation of the inflammation
	JMJD2 H3K9 demethylase	ML324	Decrease the effects of Herpes virus in mice [67]
– Histone 3 lysine 27 (H3K27)	JMJ3D (H3K27 demethylase)	GSK-J1 + GSK-J4	Inhibits LPS-induced macrophage inflammation [68]
	Lysine-specific demethylases	Compound 12d	Additive effects with HDAC inhibitors on inhibiting cell proliferation and may inhibit inflammatory cytokines [69]
DNA methylation	DNMT1 complexes		DNMT inhibitors may return T cells to a Th1 phenotype in asthma [70]
	DNMT1/PCNA	Peptide inhibitor - 163–174	Target DNA methylation at specific regions [71]
	DNMT1/USP7	Peptide inhibitor - 561–567	Target DNA methylation at specific regions [71]
	DNMT1/STAT3	Peptide inhibitor - 683–174	Target DNA methylation at specific regions [71]
	DNMT1/CFP1	Peptide inhibitor - 1081–1097	Target DNA methylation at specific regions [71]
miRNAs	miR-34 mimic	MRX34	Inhibits tumor growth [72]
	miR-122		Hepatitis C is supressed by the inhibition of miR-122 [73]
	miR-150	Nanovesicles containing miR-150	Enter effector T cells and suppressing allergic contact dermatitis and promoting antigen-specific tolerance in mice [74]
	miR-9	miR-9 antagamirs	Inhibition of miR-9 increased PP2A activity and GR nuclear translocation in macrophages and restored steroid sensitivity in multiple mouse models of steroid-resistant AHR [75]
	miR-145	miR-145 antagamir	miR-145 antagamir inhibited eosinophilic inflammation, mucus hypersecretion, Th2 cytokine production and AHR in murine model of asthma [76]
	miR-126	miR-126 antagamir	Blockade of miR-126 suppressed Th2 responses, inflammation, AHR, eosinophil recruitment and mucus hypersecretion in mouse model of asthma via suppression of GATA3 expression [77]

AHR: Airways hyper-responsiveness; BET: Bromo and extraterminal domain; GR: Glucocorticoid receptor; LPS: Lipopolysaccharide.

Hou X , WanH , AiXet al. Histone deacetylase inhibitor regulates the balance of Th17/Treg in allergic asthma . Clin. Respir. J. doi:10.1111/crj.12227 ( 2014 ) ( Epub ahead of print ).

 PubMed Web of Science ®Google Scholar

Choi SW , GatzaE , HouGet al. Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans . Blood125 ( 5 ), 815 – 819 ( 2014 ).

 PubMed Web of Science ®Google Scholar

Cheng Z , GongY , MaYet al. Inhibition of BET bromodomain targets genetically diverse glioblastoma . Clin. Cancer Res.19 , 1748 – 1759 ( 2013 ).

 PubMed Web of Science ®Google Scholar

Delmore JE , IssaGC , LemieuxMEet al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc . Cell146 ( 6 ), 904 – 917 ( 2011 ).

 PubMed Web of Science ®Google Scholar

Wei G , WeiL , ZhuJet al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells . Immunity30 ( 1 ), 155 – 167 ( 2009 ).

 PubMed Web of Science ®Google Scholar

Lewis MD , MillerSA , MiazgowiczMM , BeimaKM , WeinmannAS . T-bet’s ability to regulate individual target genes requires the conserved T-box domain to recruit histone methyltransferase activity and a separate family member-specific transactivation domain . Mol. Cell. Biol.27 ( 24 ), 8510 – 8521 ( 2007 ).

 PubMed Web of Science ®Google Scholar

Rai G , KawamuraA , Anthony TumberYLet al. ML324, a JMJD2 demethylase inhibitor with demonstrated antiviral activity . In : Probe Reports from the NIH Molecular Libraries Program . National Center for Biotechnology Information , MD, USA ( 2013 ).

 Google Scholar

Kruidenier L , ChungC , ChengZet al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response . Nature488 ( 7411 ), 404 – 408 ( 2012 ).

 PubMed Web of Science ®Google Scholar

Prusevich P , KalinJ , MingS . A selective phenelzine analogue inhibitor of histone demethylase LSD1 . ACS Chem. Biol.9 ( 6 ), 1284 – 1293 ( 2014 ).

 PubMed Web of Science ®Google Scholar

Brand S , KesperDA , TeichRet al. DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma . J. Allergy Clin. Immunol.129 ( 6 ), 1602 – 1610.e6 ( 2012 ).

 PubMed Web of Science ®Google Scholar

Cheray M , NadaradjaneA , BonnetP , RoutierS , ValletteFM , CartronP-F . Specific inhibition of DNMT1/CFP1 reduces cancer phenotypes and enhances chemotherapy effectiveness . Epigenomics6 ( 3 ), 267 – 275 ( 2014 ).

 PubMed Web of Science ®Google Scholar

Ling H , FabbriM , CalinGA . MicroRNAs and other non-coding RNAs as targets for anticancer drug development . Nat. Rev. Drug Discov.12 , 847 – 865 ( 2013 ).

 PubMed Web of Science ®Google Scholar

Janssen HLA , ReesinkHW , LawitzEJet al. Treatment of HCV infection by targeting microRNA . N. Engl. J. Med.368 , 1685 – 1694 ( 2013 ).

 PubMed Web of Science ®Google Scholar

Bryniarski K , PtakW , JayakumarAet al. Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity . J. Allergy Clin. Immunol.132 ( 1 ), 170 – 181 ( 2013 ).

 PubMed Web of Science ®Google Scholar

Li JJ , TayHL , MaltbySet al. MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity . J. Allergy Clin. Immunol.136 ( 2 ), 462 – 473 ( 2015 ).

 PubMed Web of Science ®Google Scholar

Collison A , MattesJ , PlankM , FosterPS . Inhibition of house dust mite-induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment . J. Allergy Clin. Immunol.128 ( 1 ), 160 – 167 ( 2011 ).

 PubMed Web of Science ®Google Scholar

Mattes J , CollisonA , PlankM , PhippsS , FosterPS . Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease . Proc. Natl Acad. Sci. USA106 ( 44 ), 18704 – 18709 ( 2009 ).

 PubMed Web of Science ®Google Scholar