Wide-ranging functions of E2F4 in transcriptional activation and repression revealed by genome-wide analysis.
The E2F family of transcription factors has important roles in cell cycle progression. E2F4 is an E2F family member that has been proposed to be primarily a repressor of transcription, but the scope of its binding activity and functions in transcriptional regulation is not fully known. We used ChIP sequencing (ChIP-seq) to identify around 16,000 E2F4 binding sites which potentially regulate 7346 downstream target genes with wide-ranging functions in DNA repair, cell cycle regulation, apoptosis, and other processes. While half of all E2F4 binding sites (56%) occurred near transcription start sites (TSSs), ∼20% of sites occurred more than 20 kb away from any annotated TSS. These distal sites showed histone modifications suggesting that E2F4 may function as a long-range regulator, which we confirmed by functional experimental assays on a subset. Overexpression of E2F4 and its transcriptional cofactors of the retinoblastoma (Rb) family and its binding partner DP-1 revealed that E2F4 acts as an activator as well as a repressor. E2F4 binding sites also occurred near regulatory elements for miRNAs such as let-7a and mir-17, suggestive of regulation of miRNAs by E2F4. Taken together, our genome-wide analysis provided evidence of versatile roles of E2F4 and insights into its functions.
Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, TX 78712, USA.
Bum-Kyu
BK
Lee
Akshay A
AA
Bhinge
Vishwanath R
VR
Iyer
D001665:Binding Sites; D018929:Cell Culture Techniques; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D050704:E2F4 Transcription Factor / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D058977:Molecular Sequence Annotation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation
D050704:E2F4 Transcription Factor; D035683:MicroRNAs; D012097:Repressor Proteins
EMBO J. 2004 Dec 8;23(24):4709-16
15538380
EMBO J. 2002 Nov 1;21(21):5775-86
12411495
Nucleic Acids Res. 2005 Oct 04;33(17):5533-43
16204454
Cancer Biol Ther. 2004 Dec;3(12):1208-11
15662116
Cell. 2008 Aug 8;134(3):521-33
18692474
J Biol Chem. 2003 Aug 15;278(33):30435-40
12771133
Mol Cell Biol. 1996 Mar;16(3):1047-57
8622649
Nat Genet. 2008 Jul;40(7):897-903
18552846
J Cell Physiol. 2004 May;199(2):262-73
15040009
Nat Biotechnol. 2008 Nov;26(11):1293-300
18978777
J Biol Chem. 2007 Jan 26;282(4):2130-4
17135268
Nucleic Acids Res. 2010 Jan;38(3):e13
19906703
PLoS Comput Biol. 2007 Mar 23;3(3):e39
17381235
Mol Cell Biol. 2001 Feb;21(4):1384-92
11158323
Genome Res. 2007 Nov;17(11):1550-61
17908821
Cell. 2002 Jun 28;109(7):807-9
12110178
Mol Cell Biol. 2005 Sep;25(18):8166-78
16135806
Nat Genet. 2007 May;39(5):683-7
17417638
Mol Cell. 2009 Sep 11;35(5):610-25
19748357
Nature. 2007 Aug 2;448(7153):553-60
17603471
Mol Cell. 2004 Nov 5;16(3):399-411
15525513
Nature. 2009 Dec 17;462(7275):930-4
20016602
Genes Dev. 1999 Mar 15;13(6):666-74
10090723
Cell Cycle. 2006 Mar;5(6):567-8
16582614
Genome Biol. 2003;4(5):P3
12734009
J Biol Chem. 1999 Apr 23;274(17):12009-16
10207023
PLoS One. 2007 Aug 29;2(8):e807
17726537
Cell. 2006 Dec 1;127(5):871-4
17129771
Methods Mol Biol. 2009;556:21-32
19488869
Genes Dev. 2002 Jan 15;16(2):245-56
11799067
Oncogene. 2008 Sep 11;27(40):5326-38
18504435
Nature. 2005 Jun 9;435(7043):839-43
15944709
Cell. 2002 Jul 12;110(1):19-32
12150994
Cell. 2007 May 18;129(4):823-37
17512414
Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8858-63
9671769
Science. 2009 Jun 26;324(5935):1720-3
19443739
Proc Natl Acad Sci U S A. 1997 May 13;94(10):4948-53
9144170
EMBO J. 2004 Nov 24;23(23):4615-26
15510213
Nature. 2009 May 7;459(7243):108-12
19295514
Mol Cell Biol. 1996 Apr;16(4):1436-49
8657117
Cancer Res. 2007 Oct 15;67(20):9762-70
17942906
Development. 2004 Jan;131(1):57-71
14645121
EMBO J. 2004 Mar 24;23(6):1336-47
15014447
Nat Genet. 2007 Mar;39(3):311-8
17277777
Cancer Res. 1997 Jun 15;57(12):2350-3
9192806
Int J Cancer. 2000 Jun 1;86(5):672-7
10797289
EMBO J. 1995 Sep 15;14(18):4514-22
7556094
Genome Res. 2007 Jun;17(6):818-27
17568000
PLoS Biol. 2008 Mar 18;6(3):e65
18351804
Genome Biol. 2006;7(5):R42
16737555
Mol Cell Biol. 2000 May;20(10):3417-24
10779331
Oncogene. 2009 Jan 8;28(1):140-5
18836483
Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14926-31
19706456
Nature. 2009 Feb 12;457(7231):854-8
19212405
Cell. 2007 Mar 23;128(6):1231-45
17382889
Nat Rev Genet. 2009 Oct;10(10):704-14
19763153
PLoS One. 2008 Mar 12;3(3):e1798
18335064
Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3215-20
8622916
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9574-9
10449734
Genome Res. 2004 Jan;14(1):62-6
14707170
Cell. 2005 Dec 16;123(6):1133-46
16337999
Proc Natl Acad Sci U S A. 1997 May 13;94(10):5095-100
9144196
Nat Methods. 2008 Sep;5(9):829-34
19160518
J Biol Chem. 2007 Jan 12;282(2):871-8
17121828