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1、Vol.:(0123456789)1 3Cell.Mol.Life Sci.DOI 10.1007/s00018-017-2684-9REVIEWEpigenetic regulators:multifunctional proteins modulating hypoxiainducible factor protein stability andactivityWeiboLuo1,2 YingfeiWang1,3Received:24 July 2017/Revised:26 September 2017/Accepted:9 October 2017 Springer Internati
2、onal Publishing AG 2017constitutively expressed subunit in response to low oxygen in metazoans 1.Three subunits(HIF-1,HIF-2,and HIF-3)and two subunits(HIF-1,also known as ARNT,and ARNT2)have been cloned thus far 25.Three HIF-1 mRNA transcripts are encoded by human HIF1A gene,whereas only one HIF-2 m
3、RNA transcript is transcribed from human EPAS1 gene(Fig.1).HIF-1 and HIF-2 share about 48%overall amino acid sequence identity and con-tain the same functional domains:basic helixloophelix(bHLH)domain,Per-Arnt-Sim(PAS)domain,oxygen-dependent degradation(ODD)domain,N-terminal trans-activation domain(
4、N-TAD),inhibitory domain(ID),and C-terminal transactivation domain(C-TAD)(Fig.1).A total of 19 distinct HIF-3 transcripts exist in the human genome database due to alternative mRNA splicing but only 8 variants may encode HIF-3 proteins.Human HIF-3 iso-forms 1 and 9 contain a N-TAD and a unique leuci
5、ne zipper(LZIP)domain and are shown to activate gene transcription in human cells(Fig.1)6.However,HIF-3 isoform 4 lacks the transactivation domain and LZIP domain,and func-tions as a transcriptional inhibitor for HIF-1 and HIF-2 7.HIF-1 is ubiquitously expressed,but ARNT2 expression is restricted to
6、 the brain and kidney in rat and mouse 8,9.Hundreds of genes have been discovered to be regulated by HIF in various cell types and their protein products regulate erythropoiesis,angiogenesis,metabolism,pH homeostasis,stem cell maintenance,autophagy,immune evasion,and cell migration/invasion 10.There
7、fore,HIF-1 and HIF-2 play an important role in development,physiology,and diseases,such as cancer,heart disease,sleep apnea,and trauma 10.Recent studies showed that HIF-3 overexpression causes aberrant late branching morphogenesis,alveolar forma-tion,and epithelial differentiation during lung develo
8、pment in transgenic mice 11.HIF-3 knockout impairs pulmo-nary endothelial cell proliferation and angiogenic potential Abstract The hypoxia-inducible factor(HIF)is a heter-odimeric transcription factor governing a transcriptional program in response to reduced O2 availability in metazo-ans.It contrib
9、utes to physiology and pathogenesis of many human diseases through its downstream target genes.Emerg-ing studies have shown that the transcriptional activity of HIF is highly regulated at multiple levels and the epigenetic regulators are essential for HIF-mediated transactivation.In this review,we w
10、ill discuss the comprehensive regulation of HIF transcriptional activity by different types of epigenetic regulators.Keywords Hypoxia-inducible factor Epigenetic writer Epigenetic eraser Epigenetic reader ATP-dependent chromatin remodeler Chromatin reprogramming Gene regulationIntroductionThe hypoxi
11、a-inducible factor(HIF)is a master transcrip-tional factor consisting of an inducible subunit and a Cellular and Molecular Life Sciences*Weibo Luo Weibo.LuoUTSouthwestern.edu*Yingfei Wang Yingfei.WangUTSouthwestern.edu1 Department ofPathology,UT Southwestern Medical Center,5323 Harry Hines Blvd.,Dal
12、las,TX75390,USA2 Department ofPharmacology,UT Southwestern Medical Center,5323 Harry Hines Blvd.,Dallas,TX75390,USA3 Department ofNeurology andNeurotherapeutics,UT Southwestern Medical Center,5323 Harry Hines Blvd.,Dallas,TX75390,USA W.Luo,Y.Wang 1 312,suggesting a critical role of HIF-3 in physiolo
13、gy and pathology.The transcriptional activity of HIF,particularly HIF-1 and HIF-2,is regulated at both mRNA and protein levels.Under normoxic conditions,HIF-is hydroxylated on pro-line(Pro)residues(Pro 402 and Pro 564 for human HIF-1;Pro 405 and Pro 531 for human HIF-2;Pro 406 and Pro 492 for human
14、HIF-3 isoform 9)by a family of prolyl hydroxylases(PHDs)in the presence of the cofactors(iron,-ketoglutarate,and ascorbate)and the substrate O2 13.Prolyl hydroxylated HIF-is recognized by von Hippel-Lindau(VHL),which recruits the Cullin-2/Elongin-B/C ubiquitin E3 ligase complex to induce HIF-protein
15、 degra-dation in the 26S proteasome(Fig.2)14.Under hypoxic conditions,prolyl hydroxylation of HIF-is impaired,lead-ing to stabilization of HIF-protein(Fig.2).HIF-is then translocated into the nucleus and dimerized with HIF-1.The heterodimer binds to the hypoxia response element Fig.1 The structure s
16、cheme of active human HIF-isoforms and human HIF-.The func-tional domains of each isoform are indicated.bHLH basic helix-loop-helix,PAS Per-Arnt-Sim,ODD oxygen-dependent degradation,N-TAD N-terminal transactivation domain,ID inhibitory domain,C-TAD C-terminal transactivation domain,LZIP leucine zipp
17、erFig.2 O2-dependent regulation of HIF-1 activity.Under normoxia,human HIF-1 is hydroxylated on proline(P)residues 402 and 564 by a family of prolyl hydroxylases(PHDs).Prolyl hydroxylated HIF-1 is recognized by von Hippel-Lindau(VHL),which recruits the Cullin-2/Elongin-B/C ubiquitin E3 ligase comple
18、x to induce HIF-1 protein degradation in the 26S proteasome.On the other hand,human HIF-1 is also hydroxylated on asparagine(N)803 residue by another dioxygenase factor inhibiting HIF-1(FIH-1),leading to blockade of p300 recruitment to the C-terminal transacti-vation domain of HIF-1,thereby preventi
19、ng HIF-1-dependent gene transcription.Under hypoxia,PHDs and FIH-1 lose their enzymatic activity.As such,HIF-1 protein is stabilized and the epigenetic regulators(e.g.,p300/CBP,JMJD2C)are recruited to promote HIF-1-mediated transactivationEpigenetic regulators:multifunctional proteins modulating hyp
20、oxiainducible factor1 3(5-A/GCGTG-3)across the genome to enhance gene tran-scription 15.Emerging studies have shown that epigenetic regulators,including epigenetic writers,erasers,and readers,and ATP-dependent chromatin remodelers,are essential for HIF-mediated transactivation(Table1).In this review
21、,we will discuss the comprehensive regulation of HIF transcrip-tional activity by different types of epigenetic regulators.Regulation ofHIF transcriptional activity byepigenetic writersAcetyltransferases,methyltransferases,protein kinases,and ubiquitin E3 ligases function as epigenetic writers by ad
22、d-ing epigenetic marks onto histones,DNA,or RNA.p300/CBP possess the intrinsic histone acetyltransferase activ-ity that induces histone acetylation to relax the chromatin 16.They bind to the transactivation domain of HIF-to coactivate HIF-mediated transactivation,and are responsi-ble for expression
23、of about 3050%of global HIF-1 down-stream target genes 17.Post-translational modifications of HIF-are known to modulate p300 coactivator functions.Asparagine 803 of HIF-1 is hydroxylated by factor inhib-iting HIF-1(FIH-1)under nonhypoxic conditions,thereby blocking p300 binding to HIF-1 to inhibit H
24、IF-1 transcrip-tional activity(Fig.2)18,19.In contrast,S-nitrosylation of cysteine 800 enhances p300 recruitment to HIF-1 to increase HIF-1-mediated transactivation 20.Our previous study showed that the recruitment of p300 to the hypoxia response element is enhanced by pyruvate kinase M2,a HIF coact
25、ivator 21.Several other HIF-1-interacting proteins,including CITED2,EAF2,protein kinase C zeta,FOXO3a,ORF3,p65,histone deacetylase 4(HDAC4),HDAC5,and FHL1,are also shown to regulate HIF-1-p300 interaction,leading to altered HIF-1 transcriptional activity 2229.Similarly,the histone acetyltransferase
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