Table 3.
Summary of known promoters and DNA-binding sites of Hes (A) and Hey (B) transcription factors
| Target gene | Hes/Hey protein | Method | Mode of action/binding site | Comment | References |
|---|---|---|---|---|---|
| (A) | |||||
| Direct | |||||
| Acid-α-Glucosidase | Hes1 | CAT EMSA | Class C E-box binding in first intron | Repression or activation depending on cell type | (141,142) |
| Calcipressin | Hes1 (not Hey1,2) | ChIP | DNA binding | Repression of endogenous gene expression | (143) |
| CD4 | Hes1 | EMSA Luc | N-box binding in CD4 silencer, interference with c-myb | Repression of endogenous gene in T-cells | (94,144) |
| E2F1 | Hes1 | EMSA Luc | N-box binding (homodimer and Hes1/Hey1) | Repression of endogenous gene | (145) |
| Hes1 | Hes1 | CAT FP ChIP EMSA | Direct: N-box binding Indirect: Binding to RBPJκ | Mutation of N-boxes prevents inhibition | (75,109,146,147) |
| Mash1 (Ascl1) | Hes1 | ChIP EMSA Luc | Class C E-box binding | Repression of endogenous gene. Activator by CBP binding instead of TLE1 | (68,114,115) |
| MBP | Hes5 | ChIP Luc | Direct: DNA binding and HDAC1 recruitment; Indirect: repression of Mash1 and Sox10 | Elevated myelin levels in Hes5−/− mice | (117) |
| Neurogenin3 | Hes1 | EMSA Luc | N-box binding | (148) | |
| p27(KIP1) | Hes1,6 | ChIP EMSA Luc | Class C E-box binding | Higher p27(KIP1) levels in Hes1−/− mice | (43,116) |
| PGDS | Hes1 | ChIP EMSA Luc | E-box binding | (149) | |
| Indirect | |||||
| APRE (acute phase resp. element) | Hes1,5 | EMSA Luc | Promotion of STAT3 phosphorylation by interaction with JAK2/STAT3 | Suppression of endogenous Hes1 reduces STAT3 phosphorylation | (11) |
| ATH5 | Hes1 | CAT | Competition with Ngn2 and ATH5 | Dominant negative regulator of ATH5 in retina | (150) |
| Fatty acid synthase | Hes1 | Luc | Repression of SREBP transcriptional activity | Blocks adipogenesis in preadipocytes | (46) |
| E-box promoter | Hes1 | CAT | Binding to MyoD inhibits MyoD-driven transcription | Diminished myogenic conversion of C3H10T1/2 cells induced by MyoD | (19) |
| E-box promoter | Hes1,5,7 | CAT FP Luc | Binding to E47 inhibits transcriptional activity and DNA binding | Interference with B-cell differentiation | (19,21,25,50) |
| E-box promoter | Hes1 | CAT Luc | Binding to Mash1 inhibits transcriptional activity; Rapid degradation of Mash1 | Neuronal differentiation is dependent of Hes1 downregulation | (19,115,151) |
| GATA-binding elements | Hes1 | ChIP, EMSA, Luc | Binding to GATA1 does not interfere with DNA binding, but recruitment of p300 is inhibited | Inhibition of erythroid and megakaryocytic differentiation | (85) |
| Osteopontin Osteocalcin | Hes1 | Luc | Binding to Runx2 interferes with recruitment of TLE1/ HDAC1; enhanced by Vit.-D3 and pRB | Potentiation of Runx2-induced Osteopontin expression (Activation!) | (63,92,93,139) |
| p21 | Hes1 | Luc | Repression of MASH/ E47-driven p21 expression | Suppression of endogenous gene; inhibition of proliferation | (147) |
| Ptf1-binding elements | Hes1 | Luc | Binding to Ptf1-p48 interferes with Ptf1-p48 DNA binding | Ectopic Hes1 represses acinar cell differentiation | (53,152) |
| Unknown | |||||
| DLK-Pref1 | Hes1 | Luc | ND | Repression of endogenous gene | (153) |
| Mdm2 | Hes1 | Luc | ND | Hes1 causes p53 upregulation | (154) |
| p57 | Hes1 | CAT | ND | Higher p57 levels in Hes1−/− mice | (155) |
| (B) | |||||
| Direct | |||||
| DAT1 | Hey1 | Luc, Y1H | Binding 3′ UTR | Repression of endogenous gene; upregulation in Hey1−/− mice | (156,157) |
| Vegfr2 | Hey1 | ChIP, Luc | Interference with initiator element | Repression of endogenous gene in endothelial cells | (95,96) |
| Indirect | |||||
| αMyHC | Hey1,2,L | Luc | Binding to GATA4 represses transcriptional activity | (72) | |
| ANF | Hey1,2,L | EMSA, Luc | Binding to GATA4/6 represses transcriptional activity. DNA binding of GATA can occur (72), or is prevented (88) | Repression of endogenous gene in cardiomyocytes. Ectopic expression in Hey2−/- hearts | (72,73,88) |
| APRE (acute phase resp. element) | Hey1,2 | Luc | Promotion of STAT3 phosphorylation by interaction with JAK2/STAT3 | Activation | (11) |
| E-box promoter | Hey1,2 | Luc | Prevent dimer formation of Mash1/E47 and Math3/E47 | Interference with neural differentiation | (158) |
| GATA-binding elements | Hey1 | EMSA, Luc | Binding to GATA1. No interference with DNA binding of GATA1 | Inhibition of erythroid differentiation of K562 cells | (83) |
| Myogenin | Hey1,2 | EMSA, Luc | Binding to MyoD prevents MyoD/E47 complex formation | Hey1 inhibits myogenic conversion of 10T1/2 cells induced by MyoD | (52) |
| Nkx2.5 | Hey1,2,L | Luc | Binding to GATA4 represses transcriptional activity | (72) | |
| Osteocalcin | Hey1 | Luc | Binding to Runx2 represses transcriptional activity | Hey1 downregulation enhances mineralization of MC3T3 cells | (4,91) |
| Probasin | Hey1,2 | Luc | Binding to AR and SRC1 interferes with AR/SRC1- transcriptional activity | Downregulation of Hey1 inhibits repression of AR-driven gene expression | (74) |
| Ptf1-binding elements | Hey1 | EMSA, Luc | Binding to Ptf1-p48 interferes with Ptf1-p48 DNA binding | Repression of acinar cell differentiation | (53,152) |
| SM22α SM-MHC | Hey1,2 | Luc | Binding to Myocardin or GATA6 represses transcript. activity or prevents SRF binding to CArG box | Repression of endogenous gene in smooth muscle cells and 10T1/2 cells | (76,84,89) |
| VEGF | Hey2 | EMSA, Luc | Binding to ARNT prevents ARNT/EPAS DNA binding | (28) | |
| Unknown | |||||
| Coup-TFII | Hey1,2 | Luc | Downregulation under hypoxia (Hey induction) | (9) | |
| GATA4,6 | Hey1,2,L | Luc | (73) | ||
| Hey1,2,L | Hey1,2,L | Luc | Indirect: Binding to RBPJκ | (29,38,75) | |
| Hypoxia response element | Hey1,2 | Luc | (9,159) | ||
| Mdm2 | Hey1 | Luc | Hey1 causes p53 upregulation | (154) | |
| RTA (virus) | Hey1 | ChIP, Luc | Independent of DNA binding | (160) | |
| Tbx2 | Hey1 | Luc | ND | Tbx2 repression in Hey1 or Hey2 overexpressing mice | (161) |
Abbreviations: CAT, chloramphenicol acetyl transferase assay; ChIP, chromatin immunoprecipitation; EMSA, electrophoretic mobility shift assay; FP, DNA footprint; Luc, luciferase assay.