Repression of Somatic Genes by Selective Recruitment of HDAC3 by BLIMP1 Is Essential for Mouse Primordial Germ Cell Fate Determination

Mochizuki, Kentaro; Hayashi, Yohei; Sekinaka, Tamotsu; Otsuka, Kei; Ito-Matsuoka, Yumi; Kobayashi, Hisato; Oki, Shinya; Takehara, Asuka; Kono, Toru; Osumi, Noriko; Matsui, Yasuhisa

doi:10.1016/j.celrep.2018.07.108

Cited by 15 publications

(18 citation statements)

References 34 publications

(54 reference statements)

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“…While PGCs themselves become refractory to the Bmp signalling environment, their survival and further development is thought to be critically dependent on the ability of the adjacent ExM to provide extrinsic trophic growth factors 52 . Recent in vitro experiments similarly suggest that the role of Smad1 signalling during PGCLC differentiation may be to generate somatic cells that function to promote PGCLC survival 53 . Likewise, we observe here in PGCLC aggregates localised pockets of BV + cells within p-Smad159 active regions.…”

Section: Discussionmentioning

confidence: 99%

Genetic dissection of Nodal and Bmp signalling requirements during primordial germ cell development in mouse

et al. 2019

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The essential roles played by Nodal and Bmp signalling during early mouse development have been extensively documented. Here we use conditional deletion strategies to investigate functional contributions made by Nodal, Bmp and Smad downstream effectors during primordial germ cell (PGC) development. We demonstrate that Nodal and its target gene Eomes provide early instructions during formation of the PGC lineage. We discover that Smad2 inactivation in the visceral endoderm results in increased numbers of PGCs due to an expansion of the PGC niche. Smad1 is required for specification, whereas in contrast Smad4 controls the maintenance and migration of PGCs. Additionally we find that beside Blimp1, down-regulated phospho-Smad159 levels also distinguishes PGCs from their somatic neighbours so that emerging PGCs become refractory to Bmp signalling that otherwise promotes mesodermal development in the posterior epiblast. Thus balanced Nodal/Bmp signalling cues regulate germ cell versus somatic cell fate decisions in the early posterior epiblast.

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Section: Discussionmentioning

confidence: 99%

Genetic dissection of Nodal and Bmp signalling requirements during primordial germ cell development in mouse

et al. 2019

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“…BLIMP1 mediates its role as a transcriptional repressor through the recruitment of epigenetic regulators, which include histone deacetylases HDAC1/2/3, histone methyltransferases G9A (EHMT2) and EZH2, as well as the histone demethylase LSD1, and the protein arginine methyltransferase PRMT5 (26,30,31,32,33,34,35,36). Among these, the combination of HDACs and histone methyltransferases provide the potential to convert the epigenetic state of target genes from an open to repressed chromatin state, with recruitment of G9A and EZH2 providing the capacity to mediate the establishment of repressive methylation marks at H3K9 and H3K27 residues (26,33,37,38).…”

Section: Introductionmentioning

confidence: 99%

A dichotomy of gene regulatory associations during the activated B-cell to plasmablast transition

et al. 2020

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The activated B-cell (ABC) to plasmablast transition encompasses the cusp of antibody-secreting cell (ASC) differentiation. We explore this transition with integrated analysis in human cells, focusing on changes that follow removal from CD40-mediated signals. Within hours of input signal loss, cell growth programs shift toward enhanced proliferation, accompanied by ER-stress response, and up-regulation of ASC features. Clustering of genomic occupancy for IRF4, BLIMP1, XBP1, and CTCF with histone marks identifies a dichotomy: XBP1 and IRF4 link to induced but not repressed gene modules in plasmablasts, whereas BLIMP1 links to modules of ABC genes that are repressed, but not to activated genes. Between ABC and plasmablast states, IRF4 shifts away from AP1/IRF composite elements while maintaining occupancy at IRF and ETS/IRF elements. This parallels the loss of BATF expression, which is identified as a potential BLIMP1 target. In plasmablasts, IRF4 acquires an association with CTCF, a feature maintained in plasma cell myeloma lines. Thus, shifting occupancy links IRF4 to both ABC and ASC gene expression, whereas BLIMP1 occupancy links to repression of the activation state.

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“…We demonstrated that selective recruitment of HDAC3 to somatic genes by BLIMP1 and subsequent repression of somatic gene expression are crucial for PGC fate determination ( Fig. 1) (Mochizuki et al, 2018).…”

Section: Introductionmentioning

confidence: 75%

“…We have recently established an efficient RNAi screening protocol to identify genes involved in PGC fate determination using PGCLC induction of mouse embryonic stem cells (ESCs) in culture (Mochizuki et al, 2018), and identified SETDB1 histone H3K9 tri-methyltransferase as a promising candidate. Setdb1 is constitutively expressed in epiblasts, PGCs, epiblast-like cells (EpiLCs) and PGCLCs ( Fig.…”

Section: Setdb1 Deficiency Represses Pgc Formationmentioning

confidence: 99%

“…The three transcriptional regulators BLIMP1, PRDM14 and TFAP2C are crucial for PGC establishment after E6.5. Simultaneously, the histone deacetylase HDAC3 represses somatic genes through histone H3/H4 deacetylation in cooperation with BLIMP1 to prevent somatic gene products from repressing PGC genes (Mochizuki et al, 2018).…”

Section: Involvement Of Setdb1 In Repression Of the Putative Transcrimentioning

confidence: 99%

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SETDB1 is essential for mouse primordial germ cell fate determination by ensuring BMP signaling

et al. 2018

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In mouse embryos, primordial germ cells (PGCs) are fate-determined from epiblast cells. Signaling pathways involved in PGC formation have been identified, but their epigenetic mechanisms remain poorly understood. Here, we show that the histone methyltransferase SETDB1 is an epigenetic regulator of PGC fate determination. Setdb1-deficient embryos exhibit drastic reduction of nascent PGCs. Dppa2, Otx2 and Utf1 are de-repressed whereas mesoderm development-related genes, including BMP4 signaling-related genes, are downregulated by Setdb1 knockdown during PGC-like cell (PGCLC) induction. In addition, binding of SETDB1 is observed at the flanking regions of Dppa2, Otx2 and Utf1 in cell aggregates containing PGCLCs, and trimethylation of lysine 9 of histone H3 is reduced by Setdb1 knockdown at those regions. Furthermore, DPPA2, OTX2 and UTF1 binding is increased in genes encoding BMP4 signaling-related proteins, including SMAD1. Finally, overexpression of Dppa2, Otx2 and Utf1 in cell aggregates containing PGCLCs results in the repression of BMP4 signalingrelated genes and PGC determinant genes. We propose that the localization of SETDB1 to Dppa2, Otx2 and Utf1, and subsequent repression of their expression, are crucial for PGC determination by ensuring BMP4 signaling.

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Repression of Somatic Genes by Selective Recruitment of HDAC3 by BLIMP1 Is Essential for Mouse Primordial Germ Cell Fate Determination

Cited by 15 publications

References 34 publications

Genetic dissection of Nodal and Bmp signalling requirements during primordial germ cell development in mouse

Genetic dissection of Nodal and Bmp signalling requirements during primordial germ cell development in mouse

A dichotomy of gene regulatory associations during the activated B-cell to plasmablast transition

SETDB1 is essential for mouse primordial germ cell fate determination by ensuring BMP signaling

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