The stem cell-associated transcription co-factor, ZNF521, interacts with GLI1 and GLI2 and enhances the activity of the Sonic hedgehog pathway

Scicchitano, Stefania; Giordano, Marco; Lucchino, Valeria; Montalcini, Ylenia; Chiarella, Emanuela; Aloisio, Annamaria; Codispoti, Bruna; Zoppoli, Pietro; Melocchi, Valentina; Bianchi, Fabrizio; Smaele, Enrico De; Mesuraca, Maria; Morrone, Giovanni

doi:10.1038/s41419-019-1946-x

Cited by 24 publications

(16 citation statements)

References 64 publications

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“…HDAC-mediated deacetylation of Gli (glioma-associated oncogene) promotes transcriptional activation through Hedgehog (Hh)-induced upregulation of HDAC1, and loss of HDAC activity hinders Hh pathway-dependent growth of neural progenitors and MB cells (Canettieri et al, 2010;De Smaele et al, 2011). The functional interaction between the transcription cofactor ZNF521 and GLI1 and GLI2, which enhances Hh signaling, is sensitive to HDACis (Scicchitano et al, 2019). Hh signaling stimulates granule precursor (CGP) proliferation during the early stages of postnatal cerebellar development and sustains HDAC activation leading to stimulation of CGPs.…”

Section: Medulloblastomamentioning

confidence: 99%

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Perla

Fratini

Cardoso

et al. 2020

Front. Cell Dev. Biol.

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Brain cancers are the leading cause of cancer-related deaths in children. Biological changes in these tumors likely include epigenetic deregulation during embryonal development of the nervous system. Histone acetylation is one of the most widely investigated epigenetic processes, and histone deacetylase inhibitors (HDACis) are increasingly important candidate treatments in many cancer types. Here, we review advances in our understanding of how HDACis display antitumor effects in experimental models of specific pediatric brain tumor types, i.e., medulloblastoma (MB), ependymoma (EPN), pediatric high-grade gliomas (HGGs), and rhabdoid and atypical teratoid/rhabdoid tumors (ATRTs). We also discuss clinical perspectives for the use of HDACis in the treatment of pediatric brain tumors.

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Section: Medulloblastomamentioning

confidence: 99%

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Perla

Fratini

Cardoso

et al. 2020

Front. Cell Dev. Biol.

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“…ZNF521 was initially discovered using a strategy to identify molecules that were selectively expressed in human hematopoietic stem and progenitor cells and that had a potential role in the regulation of the immature cell compartment [ 28 , 56 , 57 , 58 , 59 , 60 ]. In normal HSCs, the expression of ZNF521 rapidly diminishes, whereas in AML, and especially in those with MLL-rearrangements, expression remains elevated after oncogenic transformation [ 14 , 23 , 28 , 40 , 61 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape

Chiarella

Aloisio

Scicchitano

et al. 2021

IJMS

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Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones.

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“…Of those, five genes may be of particular interest because they are highly expressed in the brain and are also nominally associated with brain volumes. Zinc finger protein 521 (encoded by ZNF521), a protein acting as transcriptional factor, is involved in the sonic hedgehog pathway; this pathway has an essential role in the central nervous system development (Li et al, 2020;Matsubara et al, 2009;Scicchitano et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Localizing genomic regions contributing to the extremes of externalizing behavior: ADHD, aggressive and antisocial behaviors

Lopez

Pol

Franke

et al. 2019

Preprint

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Background:Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder. ADHD co-morbidities cover a broad range of traits, including aggressive behavior (AGG) and antisocial behavior (ASB). Genetics has a high percentage on the heritability of the three traits, mainly attributed to large numbers of common variants (SNPs)with very small effect sizes. We believe that some of this common variants could give insights to other elements overlapping between ADHD, AGG and ASB. Therefore, we worked at regions where these variants group are, tested how some of these regions contribute and looked for candidate genes within these. Methods:We tested for genome-wide genetic correlations using LD score regression analysis (LDSC), followed by analyses for local SNP-based heritability and cross-trait analyses for local genetic correlations. Propective genes were followed up by further investigations of gene expression patterns and genetic associations with structural subcortical brain volumes.Results: ADHD, AGG and ASB showed global positive genetic correlations among them, but also with neuroticism. Negative global genetic correlations were observed between ADHD, AGG, ASB and Primary Sclerosing Cholangitis. At the locus level, large heterogeneity between regions was observed. Cross-trait comparisons revealed 53 shared loci of interest and prioritized 20 genes which are expressed in the human brain and showed association with subcortical brain volumes. Conclusions:This study emphasizes the importance of investigating shared genetic effects between correlated traits at the locus level. Converging evidence from different cross-trait analyses approaches highlights novel candidate genes underlying the shared biological mechanisms of ADHD, AGG and ASB.

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The stem cell-associated transcription co-factor, ZNF521, interacts with GLI1 and GLI2 and enhances the activity of the Sonic hedgehog pathway

Cited by 24 publications

References 64 publications

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape

Localizing genomic regions contributing to the extremes of externalizing behavior: ADHD, aggressive and antisocial behaviors

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