Kruppel-like factors compete for promoters and enhancers to fine-tune transcription

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Ilsley, Melissa D.
Gillinder, Kevin R.
Magor, Graham W.
Huang, Stephen
Bailey, Timothy L.
Crossley, Merlin
Perkins, Andrew C.

Issue Date

2017

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Article

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Abstract

Kruppel-like factors (KLFs) are a family of 17 transcription factors characterized by a conserved DNA-binding domain of three zinc fingers and a variable N-terminal domain responsible for recruiting co-factors. KLFs have diverse functions in stem cell biology, embryo patterning, and tissue homoeostasis. KLF1 and related family members function as transcriptional activators via recruitment of co-activators such as EP300, whereas KLF3 and related members act as transcriptional repressors via recruitment of-Cterminal Binding Proteins. KLF1 directly activates the Klf3 gene via an erythroid-specific promoter. Herein, we show KLF1 and KLF3 bind common as well as unique sites within the erythroid cell genome by ChIP-seq. We show KLF3 can displace KLF1 from key erythroid gene promoters and enhancers in vivo. Using 4sU RNA labelling and RNA-seq, we show this competition results in reciprocal transcriptional outputs for >50 important genes. Furthermore, Klf3(-/-) mice displayed exaggerated recovery from anemic stress and persistent cell cycling consistent with a role for KLF3 in dampening KLF1-driven proliferation. We suggest this study provides a paradigm for how KLFs work in incoherent feed-forward loops or networks to fine-tune transcription and thereby control diverse biological processes such as cell proliferation.

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Ilsley, M. D., Gillinder, K. R., Magor, G. W., Huang, S., Bailey, T. L., Crossley, M., & Perkins, A. C. (2017). Krüppel-like factors compete for promoters and enhancers to fine-tune transcription. Nucleic Acids Research, 45(11), 6572�"6588. doi:10.1093/nar/gkx441

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Creative Commons Attribution-NonCommercial 4.0 International

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0305-1048

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