Sequence-specific Recruitment of Heterochromatin Protein 1 via Interaction with Krüppel-like Factor 11, a Human Transcription Factor Involved in Tumor Suppression and Metabolic Diseases

Lomberk, Gwen; Mathison, Angela; Grzenda, Adrienne; Seo, Seungmae; DeMars, Cathrine J.; Rizvi, Sumera; Bonilla-Vélez, Juliana; Calvo, Ézéquiel; Fernández-Zapico, Martín E.; Iovanna, Juan; Buttar, Navtej; Urrutia, Raúl

doi:10.1074/jbc.m112.342634

Cited by 50 publications

(63 citation statements)

References 56 publications

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“…We have previously deduced indirectly through the study of KLF10-deficient lymphocytes that KLF10 likely plays a role in the recruitment of PCAF to the core promoter and induction of FOXP3 in adaptive Treg cells (40), yet the direct role for KLF10 to alternatively induce or repress FOXP3 expression through the regulation of acetylation/deacetylation of regional nucleosomes is the novel discovery outlined in this report. Our data would suggest that Sin3 repressor function appears to be dominant over PCAF activation; however, we do not formally exclude the possibility that Sin3 binding normally functions as a rheostat of PCAF-induced activation as has been demonstrated for KLF11 and the recruitment of heterochromatin protein 1 (25,30). In this system, PCAF titration experiments do not affect FOXP3 gene activation (data not shown), and PCAF knockdown does not affect Sin3-mediated repression; thus, we favor the interpretation that Sin3 repressor function is dominant over PCAF activation.…”

Section: Epigenetic Regulation Of Foxp3mentioning

confidence: 59%

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: 59%

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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“…Since KLF11 has been reported to have both Sin3-HDACdependent and HP1-HMT-dependent repressor functions as well as p300-induced activation properties (Zhang et al 2001;Fernandez-Zapico et al 2009;Lomberk et al 2012;Seo et al 2012), we grouped the KLF11-binding sites into putative KLF11-activated sites (loss of H3K27ac in response to KLF11 knockdown) and putative KLF11-repressed sites (gain of H3K27ac in response to KLF11 knockdown). Our results demonstrate that putative KLF11-activated binding sites are highly enriched in the vicinity of brite-selective genes, in particular putative KLF11-activated brite-selective genes.…”

Section: Discussionmentioning

confidence: 99%

“…The generation of the (His 6 -Xpress) KLF11 and control adenoviral vectors (Ad5CMV) was described in Lomberk et al (2012). Rosiglitazone-treated hMADS adipocytes at day 15 were transduced for 6 h with ;8 3 10 9 infectious units of adenoviral particles per milliliter and 1 mg/mL poly-L-lysine in DMEM (Sigma).…”

Section: Adenoviral Overexpressionmentioning

confidence: 99%

Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers

et al. 2014

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Long-term exposure to peroxisome proliferator-activated receptor g (PPARg) agonists such as rosiglitazone induces browning of rodent and human adipocytes; however, the transcriptional mechanisms governing this phenotypic switch in adipocytes are largely unknown. Here we show that rosiglitazone-induced browning of human adipocytes activates a comprehensive gene program that leads to increased mitochondrial oxidative capacity. Once induced, this gene program and oxidative capacity are maintained independently of rosiglitazone, suggesting that additional browning factors are activated. Browning triggers reprogramming of PPARg binding, leading to the formation of PPARg ''superenhancers'' that are selective for brown-in-white (brite) adipocytes. These are highly associated with key brite-selective genes. Based on such an association, we identified an evolutionarily conserved metabolic regulator, Kruppel-like factor 11 (KLF11), as a novel browning transcription factor in human adipocytes that is required for rosiglitazone-induced browning, including the increase in mitochondrial oxidative capacity. KLF11 is directly induced by PPARg and appears to cooperate with PPARg in a feed-forward manner to activate and maintain the brite-selective gene program.

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“…EMSAs-Gel shift assays were performed as described previously (23). Briefly, a double-stranded DNA probe containing a SP1/KLF protein DNA-binding domain (5Ј-CCGGGAGC-GCGGGGCGGAGCCAGGCCGGCG-3Ј) and a doublestranded DNA probe containing a mutation in the same KLF protein DNA-binding domain (5Ј-CCGGGAGCGCAAAACA-AAGCCAGGCCGGCG-3Ј) were end-labeled with [␥-32 P]ATP using T4 polynucleotide kinase according to the manufacturer's protocol (Promega).…”

Section: Methodsmentioning

confidence: 99%

New Role for Kruppel-like Factor 14 as a Transcriptional Activator Involved in the Generation of Signaling Lipids

Assuncao

Lomberk

Cao

et al. 2014

Journal of Biological Chemistry

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Background: KLF14 has elicited attention as a master regulator of lipid metabolism. Results: KLF14 regulates chromatin remodeling on sphingosine kinase 1 gene leading to its activation and sphingosine-1-phosphate production. Conclusion: KLF14 acts as a transcriptional activator for the generation of lipid signaling molecules. Significance: This new knowledge extends the functions assigned to KLF14 and contributes to understanding its role in human diseases.

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Sequence-specific Recruitment of Heterochromatin Protein 1 via Interaction with Krüppel-like Factor 11, a Human Transcription Factor Involved in Tumor Suppression and Metabolic Diseases

Cited by 50 publications

References 56 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

Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers

New Role for Kruppel-like Factor 14 as a Transcriptional Activator Involved in the Generation of Signaling Lipids

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