The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells

Puszyk, William; Down, Thomas A.; Grimwade, David; Chomienne, Christine; Oakey, Rebecca J.; Solomon, Ellen; Guidez, Fabien

doi:10.1038/emboj.2013.118

Cited by 42 publications

(65 citation statements)

References 58 publications

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“…A gain-of-function mutation of Plzf has been found to enable mouse BM cells to increase their self-renewal capacity (40), similarly to in our previous study (10), but the molecular mechanism is poorly understood. In the present study, we found induction of Eya2 expression by transduction of PLZF-RARA and rapid and dose-dependent reduction of Eya2 following degradation of PLZF-RARA by ATRA, as well as upregulation of Eya2 through promoter binding by Plzf.…”

Section: Discussionsupporting

confidence: 74%

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

Ono

Masuya

Ishii

et al. 2017

Molecular and Cellular Biology

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PLZF is a transcription factor that confers aberrant self-renewal in leukemogenesis, and the PLZF-RARA fusion gene causes acute promyelocytic leukemia (APL) through differentiation block. However, the molecular mechanisms of aberrant self-renewal underlying PLZF-mediated leukemogenesis are poorly understood. To investigate these mechanisms, comprehensive expression profiling of mouse hematopoietic stem/progenitor cells transduced with Plzf was performed, which revealed the involvement of a key transcriptional coactivator, Eya2, a target molecule shared by Plzf and PLZF-

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Section: Discussionsupporting

confidence: 74%

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

Ono

Masuya

Ishii

et al. 2017

Molecular and Cellular Biology

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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: 75%

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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“…Among the best characterized putative PLZF targets is Kit, which encodes a type-III receptor tyrosine kinase required for spermatogonial differentiation (Besmer et al, 1993;Dym et al, 1995;Koshimizu et al, 1992 Zhang et al, 2011). Previous studies demonstrated weak PLZF interaction with the Kit promoter by ChIP in enriched populations of mouse spermatogonia and the activation of Kit mRNA in Plzf mutants (Filipponi et al, 2007;Hobbs et al, 2012;Puszyk et al, 2013), which led to the conclusion that PLZF directly represses Kit transcription. We detected a shared binding site in the first intron of Kit (active region 17206, Table S2), yet we did not find any evidence of PLZF binding to the Kit promoter in THY1 + spermatogonia.…”

Section: Discussionmentioning

confidence: 99%

The regulatory repertoire of PLZF and SALL4 in undifferentiated spermatogonia

Lovelace

Mutoji

et al. 2016

Development

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Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout adulthood through balanced self-renewal and differentiation, yet the regulatory logic of these fate decisions is poorly understood. The transcription factors Sal-like 4 (SALL4) and promyelocytic leukemia zinc finger (PLZF; also known as ZBTB16) are known to be required for normal SSC function, but their targets are largely unknown. ChIP-seq in mouse THY1+ spermatogonia identified 4176 PLZF-bound and 2696 SALL4-bound genes, including 1149 and 515 that were unique to each factor, respectively, and 1295 that were bound by both factors. PLZF and SALL4 preferentially bound gene promoters and introns, respectively. Motif analyses identified putative PLZF and SALL4 binding sequences, but rarely both at shared sites, indicating significant non-autonomous binding in any given cell. Indeed, the majority of PLZF/SALL4 shared sites contained only PLZF motifs. SALL4 also bound gene introns at sites containing motifs for the differentiation factor DMRT1. Moreover, mRNA levels for both unique and shared target genes involved in both SSC self-renewal and differentiation were suppressed following SALL4 or PLZF knockdown. Together, these data reveal the full profile of PLZF and SALL4 regulatory targets in undifferentiated spermatogonia, including SSCs, which will help elucidate mechanisms controlling the earliest cell fate decisions in spermatogenesis.

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The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells

Cited by 42 publications

References 58 publications

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

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

The regulatory repertoire of PLZF and SALL4 in undifferentiated spermatogonia

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