Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes

Chan, Ai-Leen; La, Hue M.; Legrand, Julien M. D.; Mäkelä, Juho Antti; Eichenlaub, Michael P.; Seram, Mia De; Ramialison, Mirana; Hobbs, Robin M.

doi:10.1016/j.stemcr.2017.08.001

Cited by 57 publications

(87 citation statements)

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“…Furthermore, SALL4 has been shown to localize in and regulate chromatin in cells (Böhm et al, 2007;Chan et al, 2017;Hobbs et al, 2012;Kim et al, 2017;Xiong et al, 2016), thus our observation that it directly represses KDM3A, a Histone 3 Lysine 9 (H3K9)specific Demethlyase (Gray et al, 2005), is of great interest. When we categorized all genes encoding lysine demethylases that had SALL4 CUT&RUN peaks, those that specifically encode demethylases of di-or tri-methylated H3K9 were particularly enriched, compared to those encoding demethylases of tri-methylated H3K4 ( Figure 4A).…”

Section: Sall4 Regulates the Expression Of Histone Demethylasesmentioning

confidence: 93%

Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression

Kong

Bassal

Tan

et al. 2020

Preprint

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SummaryThe zinc finger transcription factor SALL4 is highly expressed in embryonic stem cells, down-regulated in most adult tissues, but reactivated in many aggressive cancers. This unique expression pattern makes SALL4 an attractive target for designing therapeutic strategies. However, whether SALL4 binds DNA directly to regulate gene expression is unclear and many of its targets in cancer cells remain elusive. Here, through an unbiased screen of protein binding microarray (PBM) and Cleavage Under Targets and Release Using Nuclease (CUT&RUN) experiments, we identified and validated the DNA binding domain of SALL4 and its consensus binding sequence. Combined with RNA-seq analyses after SALL4 knockdown, we discovered hundreds of new SALL4 target genes that it directly regulates in aggressive liver cancer cells, including genes encoding a family of Histone 3 Lysine 9-specific Demethylases (KDMs). Taken together, these results elucidated the mechanism of SALL4 DNA binding and revealed novel pathways and molecules to target in SALL4-dependent tumors.

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Section: Sall4 Regulates the Expression Of Histone Demethylasesmentioning

confidence: 93%

Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression

Kong

Bassal

Tan

et al. 2020

Preprint

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“…To confirm these observations in the mature spermatogonial pool, we isolated undifferentiated cells (EpCAM + α6-integrin+ c-KIT-) from wildtype control and Sox3 KO adults and analysed gene expression by RT-qPCR ( Fig. 5) 38 . Within the EpCAM+ germ cell fraction of Sox3 KO testis a significantly greater proportion of cells were in the α6-integrin+ c-KIT-undifferentiated cell gate compared to controls (Fig.…”

Section: Early Postnatal Defect In 129/svj Sox3 Null Testes Spermatomentioning

confidence: 86%

“…RT-qPCR was performed using Fast Sybr Green Master Mix (Life Technologies), and run on the ABI 7500 StepOnePlus system, all reactions were completed in triplicate. Isolation and gene expression analysis of adult undifferentiated spermatogonia was performed as described 38 .…”

Section: Qpcrmentioning

confidence: 99%

SOX3 promotes generation of committed spermatogonia in postnatal mouse testes

McAninch

Mäkelä

et al. 2020

Sci Rep

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SOX3 is a transcription factor expressed within the developing and adult nervous system where it mostly functions to help maintain neural precursors. Sox3 is also expressed in other locations, notably within the spermatogonial stem/progenitor cell population in postnatal testis. Independent studies have shown that Sox3 null mice exhibit a spermatogenic block as young adults, the mechanism of which remains poorly understood. Using a panel of spermatogonial cell marker genes, we demonstrate that Sox3 is expressed within the committed progenitor fraction of the undifferentiated spermatogonial pool. Additionally, we use a Sox3 null mouse model to define a potential role for this factor in progenitor cell function. We demonstrate that Sox3 expression is required for transition of undifferentiated cells from a GFRα1+ self-renewing state to the NGN3 + transit-amplifying compartment. Critically, using chromatin immunoprecipitation, we demonstrate that SOX3 binds to a highly conserved region in the Ngn3 promoter region in vivo, indicating that Ngn3 is a direct target of SOX3. Together these studies indicate that SOX3 functions as a pro-commitment factor in spermatogonial stem/progenitor cells.

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“…The transcription factor promyelocytic leukaemia zinc finger (PLZF) is expressed by undifferentiated spermatogonia plus early differentiating cells and promotes SSC self-renewal (Buaas et al, 2004;Costoya et al, 2004;Hobbs et al, 2010). SALL4 is expressed in undifferentiated and differentiating spermatogonia, and is crucial for SSC activity plus spermatogonial differentiation (Chan et al, 2017;Hobbs et al, 2012). PLZF and SALL4 modulate responses of undifferentiated spermatogonia to niche factors by regulating pathway components (Chan et al, 2017;Hobbs et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…SALL4 is expressed in undifferentiated and differentiating spermatogonia, and is crucial for SSC activity plus spermatogonial differentiation (Chan et al, 2017;Hobbs et al, 2012). PLZF and SALL4 modulate responses of undifferentiated spermatogonia to niche factors by regulating pathway components (Chan et al, 2017;Hobbs et al, 2010). PLZF enhances sensitivity of undifferentiated spermatogonia to GDNF through mammalian target of rapamycin complex 1 (mTORC1) inhibition (Hobbs et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance

Chan

Legrand

et al. 2018

Development

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Male fertility is dependent on spermatogonial stem cells (SSCs) that self-renew and produce differentiating germ cells. Growth factors produced within the testis are essential for SSC maintenance but intrinsic factors that dictate the SSC response to these stimuli are poorly characterised. Here, we have studied the role of GILZ, a TSC22D family protein and spermatogenesis regulator, in spermatogonial function and signalling. Although broadly expressed in the germline, GILZ was prominent in undifferentiated spermatogonia and deletion in adults resulted in exhaustion of the GFRα1 SSC-containing population and germline degeneration. GILZ loss was associated with mTORC1 activation, suggesting enhanced growth factor signalling. Expression of deubiquitylase USP9X, an mTORC1 modulator required for spermatogenesis, was disrupted in mutants. Treatment with an mTOR inhibitor rescued GFRα1 spermatogonial failure, indicating that GILZ-dependent mTORC1 inhibition is crucial for SSC maintenance. Analysis of cultured undifferentiated spermatogonia lacking GILZ confirmed aberrant activation of ERK MAPK upstream mTORC1 plus USP9X downregulation and interaction of GILZ with TSC22D proteins. Our data indicate an essential role for GILZ-TSC22D complexes in ensuring the appropriate response of undifferentiated spermatogonia to growth factors via distinct inputs to mTORC1.

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Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes

Cited by 57 publications

References 50 publications

Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression

Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression

SOX3 promotes generation of committed spermatogonia in postnatal mouse testes

GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance

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