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

Abstract

Krüppel-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 cofactors. 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 C-terminal 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.

Absolute quantification of transcription factors reveals principles of gene regulation in erythropoiesis

“…In addition to TF cross-antagonisms, the model confirmed a number of previously known regulatory links including the GATA1/GATA2 regulatory loop with GATA2 activating GATA1 and GATA1 progressively repressing GATA2 (Katsumura et al, 2017), the ERG-mediated activation of RUNX1 (Taoudi et al, 2011), the TAL1-mediated activation of GATA1, GFI1b and FLI1 (Gottgens, 2015), the KLF1-mediated activation of KLF3 (Ilsley et al, 2017), the GATA2-mediated activation of HOXB4 (Fujiwara et al, 2012) and others ( Figure 3B). Furthermore, the model identified novel putative links such as TAL1-and KLF1-mediated activation of E2F4, E2F4-mediated activation of KLF3, TAL1-mediated activation of HOXB4 and others.…”

The Eupentacta fraudatrix transcriptome provides insights into regulation of cell transdifferentiation

“…Ef-KLF1/2/4 is probably a homolog of human KLF1, 2, and 4, which is confirmed by the data of Mashanov et al 24 . The KLF proteins play diverse roles in cell proliferation, differentiation, and development 37 . In particular, KLF2 and KLF4 are key TFs that maintain a stem cell-like state and somatic cell reprogramming 38 .…”

Tissue-Specific Actions of Pax6 on the Balance of Proliferation and Differentiation in Developing Forebrain are Foxg1-Dependent

“…In other words, removal of Pax6 might allow Foxg1 freer rein to drive proliferation. This could occur through direct competition between Pax6 and Foxg1 for binding, a phenomenon observed in other systems (Hong and Wu, 2010;Ilsley et al, 2017;Ngondo-Mbongo et al, 2013;Norton et al, 2017;Wan et al, 2011;Zabet and Adryan, 2013). Another possibility is that, in common with other Fox transcription factors, Foxg1 might be a chromatin remodeling (or pioneer) transcription factor that opens the chromatin to allow proteins such as Pax6 to access sites that they would not otherwise be able to bind, thereby changing its function (Golson and Kaestner, 2016;Iwafuchi-Doi and Zaret, 2016;Magnani et al, 2011).…”