The CACCC-binding protein KLF3/BKLF represses a subset of KLF1/EKLF target genes and is required for proper erythroid maturation in vivo.
The CACCC-box binding protein erythroid Krüppel-like factor (EKLF/KLF1) is a master regulator that directs the expression of many important erythroid genes. We have previously shown that EKLF drives transcription of the gene for a second KLF, basic Krüppel-like factor, or KLF3. We have now tested the in vivo role of KLF3 in erythroid cells by examining Klf3 knockout mice. KLF3-deficient adults exhibit a mild compensated anemia, including enlarged spleens, increased red pulp, and a higher percentage of erythroid progenitors, together with elevated reticulocytes and abnormal erythrocytes in the peripheral blood. Impaired erythroid maturation is also observed in the fetal liver. We have found that KLF3 levels rise as erythroid cells mature to become TER119(+). Consistent with this, microarray analysis of both TER119(-) and TER119(+) erythroid populations revealed that KLF3 is most critical at the later stages of erythroid maturation and is indeed primarily a transcriptional repressor. Notably, many of the genes repressed by KLF3 are also known to be activated by EKLF. However, the majority of these are not currently recognized as erythroid-cell-specific genes. These results reveal the molecular and physiological function of KLF3, defining it as a feedback repressor that counters the activity of EKLF at selected target genes to achieve normal erythropoiesis.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
Alister P W
AP
Funnell
Laura J
LJ
Norton
Ka Sin
KS
Mak
Jon
J
Burdach
Crisbel M
CM
Artuz
Natalie A
NA
Twine
Marc R
MR
Wilkins
Carl A
CA
Power
Tzong-Tyng
TT
Hung
José
J
Perdomo
Philip
P
Koh
Kim S
KS
Bell-Anderson
Stuart H
SH
Orkin
Stuart T
ST
Fraser
Andrew C
AC
Perkins
Richard C M
RC
Pearson
Merlin
M
Crossley
D000818:Animals; D001789:Blood Group Antigens / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004912:Erythrocytes / Q000166:cytology; D004920:Erythropoiesis; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D013154:Spleen / Q000166:cytology; D014158:Transcription, Genetic
D001789:Blood Group Antigens; D051741:Kruppel-Like Transcription Factors; C489122:TER-119 antigen, mouse; C080774:erythroid Kruppel-like factor