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Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation [RNA-Seq]

ABSTRACT: Down syndrome (DS) confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (ALL), yet the mechanisms underlying this association are undefined. We show that triplication of only 31 genes orthologous to the putative DS Critical Region (DSCR) on chr.21q22 is sufficient to promote B cell-autonomous self-renewal, in vivo maturation defects and leukemogenesis in concert with BCR-ABL. DSCR triplication results in histone H3 lysine 27 (H3K27) hypomethylation at gene promoters and a transcriptional signature characterized by de-repression of genes targeted by polycomb repressor complex 2 (PRC2), which methylates H3K27. The same signature is highly enriched among human DS-associated ALLs. Pharmacologic inhibition of PRC2 function is sufficient to confer self-renewal in wild-type B cells while inhibition of H3K27me3 demethylases completely blocks self-renewal induced by DSCR triplication. Finally, overexpression of the DSCR factor HMGN1, a nucleosome remodeling protein that suppresses H3K27me3, is necessary for self-renewal in B cells with DSCR triplication.

ORGANISM(S): Mus musculus

PROVIDER: GSE48553 | GEO | 2014/04/20

SECONDARY ACCESSION(S): PRJNA210618

REPOSITORIES: GEO

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Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation [RNA-Seq]

Project description:Down syndrome (DS) confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (ALL), yet the mechanisms underlying this association are undefined. We show that triplication of only 31 genes orthologous to the putative DS Critical Region (DSCR) on chr.21q22 is sufficient to promote B cell-autonomous self-renewal, in vivo maturation defects and leukemogenesis in concert with BCR-ABL. DSCR triplication results in histone H3 lysine 27 (H3K27) hypomethylation at gene promoters and a transcriptional signature characterized by de-repression of genes targeted by polycomb repressor complex 2 (PRC2), which methylates H3K27. The same signature is highly enriched among human DS-associated ALLs. Pharmacologic inhibition of PRC2 function is sufficient to confer self-renewal in wild-type B cells while inhibition of H3K27me3 demethylases completely blocks self-renewal induced by DSCR triplication. Finally, overexpression of the DSCR factor HMGN1, a nucleosome remodeling protein that suppresses H3K27me3, is necessary for self-renewal in B cells with DSCR triplication. Gene expression analysis of 6 samples, 3 wild-type and 3 Ts1Rhr proB cells at passage 1

2014-04-20 | E-GEOD-48553 | biostudies-arrayexpress

Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation [Affymetrix]

Project description:Children with Down syndrome (DS) have a 20-fold increased risk of developing B cell acute lymphoblastic leukemia (B-ALL). Polysomy 21 (i.e., extra copies of chr.21) is also the most frequent somatic aneuploidy among all B-ALLs. Additional B-ALLs harbor intrachromosomal amplifications of chr.21q22 (iAMP21). Yet, the mechanistic links between chr.21q22 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 is sufficient to confer murine B cell self-renewal in vitro, B cell maturation defects in vivo, and B-ALL in concert with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in murine progenitor B cells and B-ALLs, and “bivalent” genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes known to be marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q22, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo. These data implicate HMGN1 overexpression and loss of H3K27me3 in progenitor B cell transformation and suggest strategies to target leukemias with polysomy 21. Gene expression analysis of 8 samples, 4 wild-type and 4 HMGN1 overexpressing transgenic B cells

2014-04-20 | E-GEOD-55629 | biostudies-arrayexpress

Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation [ChIP-seq]

Project description:Children with Down syndrome (DS) have a 20-fold increased risk of developing B cell acute lymphoblastic leukemia (B-ALL). Polysomy 21 (i.e., extra copies of chr.21) is also the most frequent somatic aneuploidy among all B-ALLs. Additional B-ALLs harbor intrachromosomal amplifications of chr.21q22 (iAMP21). Yet, the mechanistic links between chr.21q22 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 is sufficient to confer murine B cell self-renewal in vitro, B cell maturation defects in vivo, and B-ALL in concert with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in murine progenitor B cells and B-ALLs, and ÒbivalentÓ genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes known to be marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q22, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo. These data implicate HMGN1 overexpression and loss of H3K27me3 in progenitor B cell transformation and suggest strategies to target leukemias with polysomy 21. ChIP-seq in wild-type and Ts1Rhr B cell progenitors for H3K27ac and H3K4me3

2014-04-20 | E-GEOD-48534 | biostudies-arrayexpress

Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation [Affymetrix]

2014-04-20 | GSE55629 | GEO

Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation [ChIP-seq]

Project description:Children with Down syndrome (DS) have a 20-fold increased risk of developing B cell acute lymphoblastic leukemia (B-ALL). Polysomy 21 (i.e., extra copies of chr.21) is also the most frequent somatic aneuploidy among all B-ALLs. Additional B-ALLs harbor intrachromosomal amplifications of chr.21q22 (iAMP21). Yet, the mechanistic links between chr.21q22 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 is sufficient to confer murine B cell self-renewal in vitro, B cell maturation defects in vivo, and B-ALL in concert with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in murine progenitor B cells and B-ALLs, and ÒbivalentÓ genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes known to be marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q22, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo. These data implicate HMGN1 overexpression and loss of H3K27me3 in progenitor B cell transformation and suggest strategies to target leukemias with polysomy 21.

2014-04-20 | GSE48534 | GEO

Physical and functional screening of Polycomb Repressor Complex 2 highlights novel regulators of histone H3 lysine 27 methylation status

Project description:Polycomb Repressor Complex 2 (PRC2) is a multi-protein epigenetic regulator complex that plays critical roles in early development and tissue differentiation. The complex catalyzes the methylation of histone H3 lysine 27 (H3K27). The tri-methyl state (H3K27me3) is well studied as an agent of gene repression, but more recently distinct roles for the mono- and di-methyl states have been discovered. In order to more fully understand how PRC2-associated factors might influence H3K27 status, we screened for physical associations of PRC2 subunits. Knockdown of these factors was used to produce functional interaction maps focused on H3K27 methylation, including proteins that have positive and negative effects on the levels each histone mark.

2018-04-05 | PXD005381 | Pride

Polycomb-like 3 is a PRC2 component that supports embryonic stem cell self-renewal

Project description:Polycomb repressive complex 2 (PRC2) trimethylates lysine 27 of histone H3 (H3K27me3), which regulates gene expression and controls diverse biological transitions in development, embryonic stem cell (ESC) differentiation, and cancer. Here we show that Polycomb-like 3 (Pcl3) is a component of PRC2 that promotes H3K27 trimethylation in ESCs. Chromatin immunoprecipitation and sequencing (ChIP-seq) revealed that Pcl3 co-localizes and recruits Suz12 to CpG islands. Depletion of Pcl3 decreased Suz12 binding at over 60% of PRC2 targets, including many bivalent genes. Pcl3 promotes ESC self-renewal as knockdown of Pcl3 increased spontaneous differentiation. However, Pcl3 does not affect ESC pluripotency as teratomas derived from Pcl3-depleted ESCs were able to form all three germ layers. Mutation of conserved residues within the Pcl3 TUDOR domain, a domain that recognizes methylated histones, compromises H3K27me3, suggesting that the TUDOR domain of Pcl3 is crucial for function. Thus, Pcl3 is a component of PRC2 critical for histone methylation and PRC2 recruitment.

2012-03-15 | GSE28325 | GEO

Ybx1 negatively regulates PRC2 to affect gene expression programs for neural lineage specification and neural progenitor self-renewal and differentiation [ChIP-seq]

Project description:Chromatin modifiers affect the spatiotemporal expression of gene expression programs that underlie organismal development. The Polycomb repressive complex 2 (PRC2) has emerged as a crucial player in executing neurodevelopmental programs. Here we show that the nucleic acid–binding protein Ybx1 interacts with PRC2 in human and mouse neural progenitor cells (NPCs). During early neural development in vivo, Ybx1 is required for forebrain specification and modulates mid/hindbrain growth. In NPCs, Ybx1 controls the self-renewal and neuronal differentiation. Mechanistically, Ybx1 binds PRC2 gene targets, reduces the levels of PRC2-mediated H3K27me3, and promotes the expression of genes in forebrain specification, cell proliferation, or neuronal differentiation. In Ybx1-knockout NPCs, H3K27me3 reduction by PRC2 enzymatic inhibitor or genetic depletion partially rescues the control of gene expression, self-renewal, and neuronal differentiation. Our findings suggest that Ybx1 modulates H3K27me3 by PRC2 to regulate spatiotemporal gene expression in embryonic neural development and uncover a crucial epigenetic mechanism balancing forebrain–hindbrain lineages and selfrenewal-differentiation choices in NPCs.

2020-06-16 | GSE137778 | GEO

Ybx1 negatively regulates PRC2 to affect gene expression programs for neural lineage specification and neural progenitor self-renewal and differentiation [RNA-seq]

2020-06-16 | GSE137783 | GEO

H3K27 Methyltransferase PRC2 Represses Wnt Genes to Facilitate Adipogenesis

Project description:The Wnt/b-catenin signaling inhibits adipogenesis. Genome-wide profiling studies have revealed the enrichment of histone H3K27 methyltransferase PRC2 on Wnt genes. However, the functional significance of such a direct link between the two types of developmental regulators in mammalian cells, and the role of PRC2 in adipogenesis, remain unclear. Here we show PRC2 and its H3K27 methyltransferase activity are required for adipogenesis. PRC2 directly represses Wnt1, 6, 10a and 10b genes in preadipocytes and during adipogenesis. Deletion of the enzymatic Ezh2 subunit of PRC2 eliminates H3K27me3 on Wnt promoters and de-represses Wnt expression, which leads to activation of Wnt/b-catenin signaling and inhibition of adipogenesis. Ectopic expression of the wild type Ezh2, but not the enzymatically inactive F667I mutant, prevents the loss of H3K27me3 and the defects in adipogenesis in Ezh2-/- preadipocytes. The adipogenesis defects in Ezh2-/- cells can be rescued by expression of adipogenic transcription factors PPARa, C/EBPb, or inhibitors of Wnt/b-catenin signaling. Interestingly, Ezh2-/- cells show marked increase of H3K27 acetylation globally as well as on Wnt promoters. These results indicate that H3K27 methyltransferase PRC2 directly represses Wnt genes to facilitate adipogenesis, and suggest that acetylation and trimethylation on H3K27 play opposing roles in regulating Wnt expression. To identify additional PRC2-regulated genes in preadipocytes, we performed microarray analysis in Ezh2flox/flox preadipocytes infected with retroviruses expressing Cre or vector alone.

2010-03-19 | E-GEOD-20054 | biostudies-arrayexpress

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