Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells.
The transcription factor PU.1 occupies a central role in controlling myeloid and early B-cell development, and its correct lineage-specific expression is critical for the differentiation choice of hematopoietic progenitors. However, little is known of how this tissue-specific pattern is established. We previously identified an upstream regulatory cis element whose targeted deletion in mice decreases PU.1 expression and causes leukemia. We show here that the upstream regulatory cis element alone is insufficient to confer physiologic PU.1 expression in mice but requires the cooperation with other, previously unidentified elements. Using a combination of transgenic studies, global chromatin assays, and detailed molecular analyses we present evidence that PU.1 is regulated by a novel mechanism involving cross talk between different cis elements together with lineage-restricted autoregulation. In this model, PU.1 regulates its expression in B cells and macrophages by differentially associating with cell type-specific transcription factors at one of its cis-regulatory elements to establish differential activity patterns at other elements.
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Mathias
M
Leddin
Chiara
C
Perrod
Maarten
M
Hoogenkamp
Saeed
S
Ghani
Salam
S
Assi
Sven
S
Heinz
Nicola K
NK
Wilson
George
G
Follows
Jörg
J
Schönheit
Lena
L
Vockentanz
Ali M
AM
Mosammam
Wei
W
Chen
Daniel G
DG
Tenen
David R
DR
Westhead
Berthold
B
Göttgens
Constanze
C
Bonifer
Frank
F
Rosenbauer
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D015139:Blotting, Southern; D015153:Blotting, Western; D002469:Cell Separation; D025461:Feedback, Physiological / Q000502:physiology; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1
Genome Res. 2006 Oct;16(10):1310-9
16963707
Development. 2007 Nov;134(21):3815-25
17913791
Blood. 2009 Jul 9;114(2):299-309
19339695
Nat Genet. 2004 Jun;36(6):624-30
15146183
Blood. 2009 Jun 4;113(23):5783-92
19171877
Nature. 1988 Jan 21;331(6153):277-80
2827041
Genes Dev. 2002 Jul 1;16(13):1721-37
12101129
J Biol Chem. 2005 Jul 29;280(30):27552-60
15923188
Int J Hematol. 2002 Jun;75(5):466-72
12095145
Nat Immunol. 2010 Jul;11(7):635-43
20543837
Science. 1994 Sep 9;265(5178):1573-7
8079170
Genome Res. 2007 Jun;17(6):691-707
17567990
Nat Genet. 2009 Nov;41(11):1207-15
19801979
Mol Cell Biol. 2005 Apr;25(7):2832-45
15767686
Annu Rev Biochem. 1988;57:159-97
3052270
Nat Genet. 2006 Jan;38(1):27-37
16311598
J Exp Med. 2005 Jan 17;201(2):221-31
15657291
Blood. 2001 Nov 15;98(10):2958-65
11698277
EMBO J. 1998 Oct 1;17(19):5744-56
9755174
Blood. 2007 Nov 1;110(9):3136-42
17671233
Nature. 2000 Mar 9;404(6774):193-7
10724173
J Exp Med. 2002 Jun 3;195(11):1387-95
12045237
Nature. 2009 Sep 10;461(7261):199-205
19741700
Mol Cell Biol. 2010 Oct;30(20):4922-39
20696839
EMBO J. 1996 Oct 15;15(20):5647-58
8896458
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1486-91
16432184
Oncogene. 2006 Mar 2;25(9):1349-57
16247445
Cell. 1990 Apr 6;61(1):113-24
2180582
J Exp Med. 2005 May 2;201(9):1487-502
15867096
Blood. 2005 Apr 1;105(7):2707-16
15598817
Oncogene. 2002 May 13;21(21):3377-90
12032776
Mol Cell Biol. 2007 Nov;27(21):7425-38
17785440
Immunity. 2002 Nov;17(5):665-76
12433372
Mol Cell. 2010 May 28;38(4):576-89
20513432
Immunity. 2010 Mar 26;32(3):317-28
20206554
Nat Rev Immunol. 2007 Feb;7(2):105-17
17259967
Nat Genet. 2007 Mar;39(3):311-8
17277777
Genome Res. 2008 Nov;18(11):1851-8
18714091
Cell Stem Cell. 2009 Nov 6;5(5):554-66
19896445
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W253-8
17478497
Cell. 2004 May 28;117(5):663-76
15163413
Bioinformatics. 2008 Aug 1;24(15):1729-30
18599518
Immunity. 2002 Feb;16(2):285-96
11869688
Nat Rev Genet. 2000 Oct;1(1):57-64
11262875
Immunity. 2010 May 28;32(5):628-41
20510871
Blood. 2008 Sep 1;112(5):1673-82
18552207
Blood. 2005 Sep 1;106(5):1590-600
15914556
Blood. 2004 Dec 1;104(12):3437-44
15304397
Nat Immunol. 2003 Oct;4(10):1029-36
12958595
Genome Res. 2008 Sep;18(9):1422-32
18687876
Cell. 2006 Aug 25;126(4):755-66
16923394