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Molecular and Cellular Biology Volume 32, 2012 - Issue 16
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Article

The CACCC-Binding Protein KLF3/BKLF Represses a Subset of KLF1/EKLF Target Genes and Is Required for Proper Erythroid Maturation In Vivo

Alister P. W. Funnella School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
,
Laura J. Nortona School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
,
Ka Sin Maka School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
,
Jon Burdacha School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
,
Crisbel M. Artuza School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
,
Natalie A. Twinea School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
,
Marc R. Wilkinsa School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
,
Carl A. Powerb Mark Wainwright Analytical Centre, University of New South Wales, Sydney, New South Wales, Australia
,
Tzong-Tyng Hungb Mark Wainwright Analytical Centre, University of New South Wales, Sydney, New South Wales, Australia
,
José Perdomoc Department of Medicine, St. George Clinical School, University of New South Wales, Sydney, New South Wales, Australia
,
Philip Kohd Division of Molecular Genetics and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
,
Kim S. Bell-Andersone School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia
,
Stuart H. Orkinf Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
,
Stuart T. Fraserg Discipline of Physiology, School of Medical Science, University of Sydney, Sydney, New South Wales, Australia
,
Andrew C. Perkinsd Division of Molecular Genetics and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia;h Mater Medical Research Institute, South Brisbane, Queensland, Australia
,
Richard C. M. Pearsona School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
&
Merlin Crossleya School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, AustraliaCorrespondence[email protected]
 show all
Pages 3281-3292 | Received 07 Feb 2012, Accepted 26 May 2012, Published online: 20 Mar 2023
 
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Abstract

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.

View publisher note:
Articles of Significant Interest Selected from This Issue by the Editors

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00173-12.

ACKNOWLEDGMENTS

This work is supported by funding from the National Health and Medical Research Council and the Australian Research Council.

A.P.W.F. designed and performed research, analyzed data, and wrote the paper; L.J.N., K.S.M., P.K., J.B., C.M.A., C.A.P., and T.H. performed research and analyzed data; N.A.T., M.R.W., and K.S.B.-A. analyzed data; J.P., S.H.O., S.T.F., and A.C.P. designed research and analyzed data; R.C.M.P. designed research, analyzed data, and wrote the paper; and M.C. devised the concept and research, analyzed data, and wrote the paper.

We declare that no competing financial interests exist.

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