Detailed Structural-Functional Analysis of the Krüppel-like Factor 16 (KLF16) Transcription Factor Reveals Novel Mechanisms for Silencing Sp/KLF Sites Involved in Metabolism and Endocrinology

Daftary, Gaurang S.; Lomberk, Gwen; Buttar, Navtej; Allen, Thomas W.; Grzenda, Adrienne; Zhang, Jin‐San; Zheng, Ye; Mathison, Angela; Gada, R.; Calvo, Ézéquiel; Iovanna, Juan; Billadeau, Daniel D.; Prendergast, Franklyn G.; Urrutia, Raúl

doi:10.1074/jbc.m111.266007

Cited by 40 publications

(47 citation statements)

References 50 publications

(80 reference statements)

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“…One would expect the Sin3-mediated mechanism to be inactivated in order for KLF10 to express PCAF-induced activation. Inactivation may occur through KLF10 posttranslational modifications downstream of lymphocyte cell signaling cascades in a similar manner to Sin3-binding disruption to KLF11 (12) and KLF16 (8).…”

Section: Epigenetic Regulation Of Foxp3mentioning

confidence: 99%

“…Several key pieces of data are important to consider within the context of this report. First, the SID of the closely related family member KLF16 bears a tyrosine residue (Y10) that is a Src-family tyrosine kinase target and upon which phosphorylation clearly regulates function (8). Second, ERK-induced phosphorylation of KLF11, the most closely related family member to KLF10, has been clearly demonstrated to disrupt Sin3 binding and repressor function (11).…”

Section: Epigenetic Regulation Of Foxp3mentioning

confidence: 99%

“…The three-dimensional structure of the KLF10 SID complexed with the Sin3-paired amphipathic helix domain 2 (PAH2) domain was determined using a similar approach previously described for both KLF11 (41) and KLF16 (8). Briefly, we utilized the Sin3a-HBP1 complex (Protein Data Bank code 1s5r) as a template for KLF10-Sin3 SID homology-based modeling.…”

Section: Cloning Of the Foxp3 Promoter Construct And The Development mentioning

confidence: 99%

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Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene

Xiong

Svingen

Sarmento

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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However, chromatin-mediated mechanisms that underlie these events in T regulatory cells remain to be fully characterized. Here, we report that inducibility of FOXP3, a key transcription factor for the development of T regulatory cells, depends upon Kruppel-like factor 10 (KLF10) interacting with two antagonistic histone-modifying systems. We utilized chromatin immunoprecipitation, genome-integrated reporter assays, and functional domain KLF10 mutant proteins, to characterize reciprocal interactions between this transcription factor and either the Sin3-histone deacetylase complex or the histone acetyltransferase, p300/CBP-associated factor (PCAF). We characterize a Sin3-interacting repressor domain on the NH2 terminus of KLF10, which works to limit the activating function of this transcription factor. Indeed, inactivation of this Sin3-interacting domain renders KLF10 able to physically associate with PCAF as to induce FOXP3 gene transcription. We show that this biochemical data derived from studying our genome-integrated reporter cell system are recapitulated in primary murine lymphocytes. Collectively, these results advance our understanding of how a single transcription factor, namely KLF10, functions as a toggle to integrate antagonistic signals regulating FOXP3 and, thus, immune activation.T regulatory cell; KLF10; PCAF; Sin3; FOXP3 FOXP3ϩ T REGULATORY (TREG) cells may develop outside the thymus, generally in response to transforming growth factor ␤ (TGF␤) and antigen to become critically important in intestinal immunologic homeostasis (adaptive Treg cells) (2,6,7,22,23,26). Dysregulation of the transcription factor FOXP3, a key initiator of the Treg differentiation and functional program, leads to immune dysregulation in both mice (scurfy mouse) and humans (IPEX-immune polyendocrinopathy enteritis and X-linked-syndrome) (16,38). While advances in T lymphocyte biology indicate the importance of TGF␤-induced activated T cells in both the induction (Th17 cells) and regulation (FOXP3ϩ Treg cells) of intestinal inflammation (3), the precise mechanistic events integrating the TGF␤ signal to intracellular pathways that function as inducers or regulators of inflammation are not fully defined.To identify these pathways, we recently characterized a role for a TGF␤-inducible Kruppel-like factor (KLF10) in silencing FOXP3 leading to enhanced colitis susceptibility, while providing mechanistic insights into how these functions require novel chromatin coupling events (40). These studies defined the importance of p300/CBP-associated factor (PCAF), a histone acetyltransferase (HAT) recruited by KLF10 to the FOXP3 transcriptional regulatory regions that are critical for the induction of this gene (40). In the experiments reported here, we build upon our previous discovery and demonstrate that KLF10 possesses the dual capacity to either positively or negatively regulate FOXP3 through its differential association with PCAF or the histone deacetylase binding protein Sin3, respectively. Collectively, these results increase our u...

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Section: Epigenetic Regulation Of Foxp3mentioning

confidence: 99%

Section: Epigenetic Regulation Of Foxp3mentioning

confidence: 99%

Section: Cloning Of the Foxp3 Promoter Construct And The Development mentioning

confidence: 99%

See 1 more Smart Citation

Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene

Xiong

Svingen

Sarmento

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…1) that contains a CtBP recognition motif (Lahiri and Zhao, 2012;Schuierer et al, 2001;Turner and Crossley, 1998;van Vliet et al, 2000), and KLF9, 10, 11, 13, 14 and 16 contain a Cabut domain in their N-terminal section ( Fig. 1) that encompasses a Sin3 interaction domain (SID) and is referred to as a transcriptional regulatory repression domain (Cook et al, 1999;Daftary et al, 2012;Kaczynski et al, 2001Kaczynski et al, , 2002Lomberk et al, 2013;Truty et al, 2009;Zhang et al, 2001a). Nuclear localization signals (NLSs) have also been identified in several KLFs (Fig.…”

Section: Introductionmentioning

confidence: 99%

Krüppel-like factors in mammalian stem cells and development

2017

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Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors that are found in many species. Recent studies have shown that KLFs play a fundamental role in regulating diverse biological processes such as cell proliferation, differentiation, development and regeneration. Of note, several KLFs are also crucial for maintaining pluripotency and, hence, have been linked to reprogramming and regenerative medicine approaches. Here, we review the crucial functions of KLFs in mammalian embryogenesis, stem cell biology and regeneration, as revealed by studies of animal models. We also highlight how KLFs have been implicated in human diseases and outline potential avenues for future research.

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“…Previous studies have shown that growth factors functionally modulate KLFs by triggering posttranslational modification or cytoplasm-to-nucleus shuttling of KLFs (Lomberk and Urrutia, 2005;Daftary et al, 2012). For example, the phosphorylation of KLF16 (one of the KLF family members) modulates its transcriptional activity assessed by reporter gene expression, and certain serum factors have been shown to significantly decrease the nuclear translocation of KLF16 and its transcriptional activity (Daftary et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Krüppel-Like Factor 9 Promotes Hepatic Cytochrome P450 2D6 Expression during Pregnancy in CYP2D6-Humanized Mice

et al. 2014

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Cytochrome P450 2D6 (CYP2D6), a major drug-metabolizing enzyme, is responsible for metabolism of approximately 25% of marketed drugs. Clinical evidence indicates that metabolism of CYP2D6 substrates is increased during pregnancy, but the underlying mechanisms remain unclear. To identify transcription factors potentially responsible for CYP2D6 induction during pregnancy, a panel of genes differentially expressed in the livers of pregnant versus nonpregnant CYP2D6-humanized (tg-CYP2D6) mice was compiled via microarray experiments followed by realtime quantitative reverse-transcription polymerase chain reaction (qRT-PCR) verification. As a result, seven transcription factorsactivating transcription factor 5 (ATF5), early growth response 1 (EGR1), forkhead box protein A3 (FOXA3), JUNB, Krüppel-like factor 9 (KLF9), KLF10, and REV-ERBa-were found to be up-regulated in liver during pregnancy. Results from transient transfection and promoter reporter gene assays indicate that KLF9 itself is a weak transactivator of CYP2D6 promoter but significantly enhances CYP2D6 promoter transactivation by hepatocyte nuclear factor 4 (HNF4a), a known transcriptional activator of CYP2D6 expression. The results from deletion and mutation analysis of CYP2D6 promoter activity identified a KLF9 putative binding motif at -22/-14 region to be critical in the potentiation of HNF4a-induced transactivation of CYP2D6. Electrophoretic mobility shift assays revealed a direct binding of KLF9 to the putative KLF binding motif. Results from chromatin immunoprecipitation assay showed increased recruitment of KLF9 to CYP2D6 promoter in the livers of tg-CYP2D6 mice during pregnancy. Taken together, our data suggest that increased KLF9 expression is in part responsible for CYP2D6 induction during pregnancy via the potentiation of HNF4a transactivation of CYP2D6.

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Detailed Structural-Functional Analysis of the Krüppel-like Factor 16 (KLF16) Transcription Factor Reveals Novel Mechanisms for Silencing Sp/KLF Sites Involved in Metabolism and Endocrinology

Cited by 40 publications

References 50 publications

Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene

Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene

Krüppel-like factors in mammalian stem cells and development

Krüppel-Like Factor 9 Promotes Hepatic Cytochrome P450 2D6 Expression during Pregnancy in CYP2D6-Humanized Mice

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