BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs

Sadler, Anthony John; Rossello, Fernando; Yu, Liang; Deane, James A.; Yuan, Xiangliang; Wang, Die; Irving, Aaron T.; Kaparakis‐Liaskos, Maria; Gantier, Michael P.; Ying, Hangjie; Yim, Howard Chi Ho; Hartland, Elizabeth L.; Notini, Amanda J.; Boer, Suzan de; White, Stefan J.; Mansell, Ashley; Liu, Junping; Watkins, D. Neil; Gerondakis, Steve; Williams, Bryan R.G.; Xu, Dakang

doi:10.1073/pnas.1409728112

Cited by 58 publications

(56 citation statements)

References 37 publications

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“…Taken together, these results explain how PLZF alone can function at different levels to recruit a broad effector gene program. Although PLZF contains nine zinc fingers at its carboxy terminus, some of which have been proposed to bind DNA in a sequence-specific manner in myeloid cell types, ChIP-seq analyses have not been reported, and a consensus binding sequence has not emerged (32)(33)(34)(35)(36). Our study suggests the possibility that rather than binding a specific consensus motif, PLZF may occupy regulatory regions associated with other canonical lymphoid transcription factors, such as ETS, E protein, and RUNX.…”

Section: Discussionmentioning

confidence: 76%

Multiple layers of transcriptional regulation by PLZF in NKT-cell development

Mao

Constantinides

Mathew

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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The transcription factor PLZF [promyelocytic leukemia zinc finger, encoded by zinc finger BTB domain containing 16 (Zbtb16)] is induced during the development of innate and innate-like lymphocytes to direct their acquisition of a T-helper effector program, but the molecular mechanisms involved are poorly understood. Using biotinylationbased ChIP-seq and microarray analysis of both natural killer T (NKT) cells and PLZF-transgenic thymocytes, we identified several layers of regulation of the innate-like NKT effector program. First, PLZF bound and regulated genes encoding cytokine receptors as well as homing and adhesion receptors; second, PLZF bound and activated T-helperspecific transcription factor genes that in turn control T-helper-specific programs; finally, PLZF bound and suppressed the transcription of Bach2, a potent general repressor of effector differentiation in naive T cells. These findings reveal the multilayered architecture of the transcriptional program recruited by PLZF and elucidate how a single transcription factor can drive the developmental acquisition of a broad effector program.atural killer (NK) T (NKT) cells are a conserved population of innate-like T cells that express CD1d-restricted semi-invariant αβ T-cell receptors (TCRs), using mostly the Vα14-Jα18 chain in mouse (Vα24-Jα18 in human) combined with variable Vβ8, Vβ7, and Vβ2 (Vβ11 in human) chains, which confer recognition of conserved self and foreign lipids (1-3). NKT cell precursors arise during thymic development at the CD4 + CD8+ double-positive stage and undergo massive expansion on interaction with CD1d ligands expressed on cortical thymocytes. They also characteristically acquire an effector CD44 hi CD62L lo phenotype along with receptors of the NK cell lineage. The innate-like effector functions of NKT cells are illustrated by the cells' ability to promptly secrete large quantities of both IL-4 and IFN-γ either after TCR activation or on exposure to tissue-and antigen-presenting cell-derived cytokines, such as IL-25+IL-33 and IL-12+IL-18, respectively. Whereas C57BL/6 mice produce predominantly NKT cells with a T-bet-dependent type 1 helper phenotype (NKT1), other strains, including BALB/c, also express substantial populations of so-called NKT2 and NKT17 cells with polarized type 2 and type 17 helper programs controlled by GATA3 and RORγt, respectively.The BTB-zinc finger transcription factor PLZF (promyelocytic leukemia zinc finger, encoded by Zbtb16), is specifically expressed in NKT cells, but not in conventional T cells or NK cells, and directs the acquisition of several key components of the NKT cell effector program during development, including cytokine and migration properties (4-7). Mutations or deletion of Zbtb16 abrogate both the expansion and the effector-memory differentiation of NKT cells, resulting in reversal to a naive phenotype and redistribution to the lymph nodes and circulating blood. PLZF expression is also essential for the development of other innate-like T cells, including MR1-specific semi-invariant ...

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Section: Discussionmentioning

confidence: 76%

Multiple layers of transcriptional regulation by PLZF in NKT-cell development

Mao

Constantinides

Mathew

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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“…ZBTB has been shown to regulate autophagy by mediating the proteasomal degradation of Atg14L (35). ZBTB16 is also involved in type 2 innate lymphoid cell function (63), NKT cell differentiation (64), and regulation of inflammatory signaling (65). MAFB is associated with macrophage differentiation (36,66).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Liu¹,

Naito²,

Liu³

et al. 2017

JCI Insight

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IntroductionCrohn's disease (CD) and ulcerative colitis are 2 main classical types of inflammatory bowel disease (IBD) (1, 2). The etiology of IBD involves genetic susceptibility and environmental triggers. Over 200 single nucleotide polymorphisms (SNPs) have been associated with susceptibility to IBD (3-7). This complex genetic network indicates that IBD likely encompasses more than the 2 classical subtypes. Therefore, novel, rationally designed biomarkers that can lead to disease stratification and personalized treatments are needed (8). One candidate method to subtype CD is to define the morphological patterns of small intestinal Paneth cells based on the intracellular distribution of granules containing antimicrobial proteins (Paneth cell phenotypes) (7). Paneth cells are specialized secretory cells located at the bases of the crypts of Lieberkühn in the small intestine (9-11). These cells produce a wide repertoire of antimicrobial BACKGROUND. Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn's disease (CD) patients, and are associated with autophagy-associated ATG16L1 and NOD2 variants. We hypothesized that genetic determinants of Paneth cell phenotype in other ethnic CD cohorts are distinct but also involved in autophagy.

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“…A role of ZBTB16 in the control of inflammation is emerging. ZBTB16 would form a co-repressor complex with HDAC3 and NF-κB in order to moderate the inflammatory program [51, 52]. A possible function of ZBTB16 in placenta physiopathology remains to be explored, however a recent study linked it to hydatidiform molar pregnancies through its physical interaction with NLRP7 [53].…”

Section: Discussionmentioning

confidence: 99%

An Integrative Analysis of Preeclampsia Based on the Construction of an Extended Composite Network Featuring Protein-Protein Physical Interactions and Transcriptional Relationships

Vaiman

Miralles

2016

PLoS ONE

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Preeclampsia (PE) is a pregnancy disorder defined by hypertension and proteinuria. This disease remains a major cause of maternal and fetal morbidity and mortality. Defective placentation is generally described as being at the root of the disease. The characterization of the transcriptome signature of the preeclamptic placenta has allowed to identify differentially expressed genes (DEGs). However, we still lack a detailed knowledge on how these DEGs impact the function of the placenta. The tools of network biology offer a methodology to explore complex diseases at a systems level. In this study we performed a cross-platform meta-analysis of seven publically available gene expression datasets comparing non-pathological and preeclamptic placentas. Using the rank product algorithm we identified a total of 369 DEGs consistently modified in PE. The DEGs were used as seeds to build both an extended physical protein-protein interactions network and a transcription factors regulatory network. Topological and clustering analysis was conducted to analyze the connectivity properties of the networks. Finally both networks were merged into a composite network which presents an integrated view of the regulatory pathways involved in preeclampsia and the crosstalk between them. This network is a useful tool to explore the relationship between the DEGs and enable hypothesis generation for functional experimentation.

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BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs

Cited by 58 publications

References 37 publications

Multiple layers of transcriptional regulation by PLZF in NKT-cell development

Multiple layers of transcriptional regulation by PLZF in NKT-cell development

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

An Integrative Analysis of Preeclampsia Based on the Construction of an Extended Composite Network Featuring Protein-Protein Physical Interactions and Transcriptional Relationships

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