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The significance of PAX5 in Merkel cell carcinoma (RNA-Seq I)

ABSTRACT: Merkel cell carcinoma (MCC) is a highly malignant skin cancer that expresses epithelial-, neuroendocrine-, and lymphoid-associated genes. Here, we focused on B-cell differentiation, which is characterised by the co-expression of PAX5 and TdT. PAX5 is the master regulator of B-cell commitment and is expressed in 65% of MCC cases. Yet, little is known about the underlying molecular biology of the frequently reported PAX5 expression in MCC. Multi-omics analyses, including RNA next-generation sequencing, RT-qPCR, immunohistochemistry, and western blotting, were performed to assess PAX5 expression in MCC. Differential DNA methylation analysis at 61,043 PAX5 binding sites in enhancer and promoter elements was performed to detect differences between n=14 MCC tissues and n=91 various normal B-cell populations. RNA analysis revealed full-length PAX5 expression in MCC at the transcriptional level using both PAX5 transcription start sites. PAX5 protein expression was found in 40 of 41 MCCs and six out of seven MCC cell lines. DNA methylation array analysis revealed 1,084 hypermethylated loci of enhancer and promoter elements located in PAX5 binding sites in MCC. Of these, 702 loci were associated with 257 genes which are not expressed. The PAX5-associated regulatory elements of these 257 genes were enriched for interferon regulatory factor 4 (IRF4) and SPi-proto-oncogene (SPI1) binding motifs. Neither IRF4 or SPI1 could be detected in MCC on a RNA or protein level. Thus, because of the absence of these transcription factors we conclude that full length PAX5 alone cannot induce B-cell differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214946 | GEO | 2025/01/31

REPOSITORIES: GEO

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The significance of PAX5 in Merkel cell carcinoma (RNA-Seq II)

Project description:Merkel cell carcinoma (MCC) is a highly malignant skin cancer that expresses epithelial-, neuroendocrine-, and lymphoid-associated genes. Here, we focused on B-cell differentiation, which is characterised by the co-expression of PAX5 and TdT. PAX5 is the master regulator of B-cell commitment and is expressed in 65% of MCC cases. Yet, little is known about the underlying molecular biology of the frequently reported PAX5 expression in MCC. Multi-omics analyses, including RNA next-generation sequencing, RT-qPCR, immunohistochemistry, and western blotting, were performed to assess PAX5 expression in MCC. Differential DNA methylation analysis at 61,043 PAX5 binding sites in enhancer and promoter elements was performed to detect differences between n=14 MCC tissues and n=91 various normal B-cell populations. RNA analysis revealed full-length PAX5 expression in MCC at the transcriptional level using both PAX5 transcription start sites. PAX5 protein expression was found in 40 of 41 MCCs and six out of seven MCC cell lines. DNA methylation array analysis revealed 1,084 hypermethylated loci of enhancer and promoter elements located in PAX5 binding sites in MCC. Of these, 702 loci were associated with 257 genes which are not expressed. The PAX5-associated regulatory elements of these 257 genes were enriched for interferon regulatory factor 4 (IRF4) and SPi-proto-oncogene (SPI1) binding motifs. Neither IRF4 or SPI1 could be detected in MCC on a RNA or protein level. Thus, because of the absence of these transcription factors we conclude that full length PAX5 alone cannot induce B-cell differentiation.

2025-01-31 | GSE214947 | GEO

The significance of PAX5 in Merkel cell carcinoma (Methylation BeadChip)

2025-01-31 | GSE214944 | GEO

The B cell identity factor Pax5 regulates distinct transcriptional programs in early and late B lymphopoiesis

Project description:Pax5 controls the identity and development of B cells by repressing lineage-inappropriate genes and activating B-cell-specific genes. Here, we used genome-wide approaches to identify Pax5 target genes in pro-B and mature B cells. In these cell types, Pax5 bound to 40% of the cis- regulatory elements defined by mapping Dnase I hypersensitive (DHS) sites, transcription start sites and histone modifications. Although Pax5 bound to 8,000 target genes, it regulated only 4% of them in pro-B and mature B cells by inducing enhancers at activated genes and eliminating DHS sites at repressed genes. Pax5-regulated genes in pro-B cells account for 23% of all expression changes occurring between common lymphoid progenitors and committed pro-B cells, which identifies Pax5 as an important regulator of this developmental transition. Regulated Pax5 target genes minimally overlap in pro-B and mature B cells, which reflects massive expression changes between these cell types. Hence, Pax5 controls B cell identity and function by regulating distinct target genes in early and late B lymphopoiesis. 44 samples (16 RNA-seq, 15 ChIP-seq, 6 DHS-seq, 5 Bio-ChIP-seq, 2 CAGE-seq). All but four samples in in 2 biological replicates (8819, 8275, 8095, 8666). WT and experimental samples are provided.

2012-06-14 | E-GEOD-38046 | biostudies-arrayexpress

The B cell identity factor Pax5 regulates distinct transcriptional programs in early and late B lymphopoiesis

2012-06-14 | GSE38046 | GEO

IGH analysis in pro-B cells with H3K4me3, H3K4me2, H3K9ac, H3K27me3, Pax5 and CTCF [ChIP-chip]

Project description:VH-DJH recombination of the immunoglobulin heavy-chain (Igh) locus is temporally and spatially controlled during early B-cell development, and yet no regulatory elements other than the VH gene promoters have been identified throughout the entire 2.5-Mb VH gene cluster. Here we discovered novel regulatory sequences that are interspersed in the distal VH gene region. These conserved repeat elements were characterized by the presence of Pax5-dependent active chromatin, the binding of Pax5, E2A, CTCF and Rad21 as well as by Pax5-dependent antisense transcription in pro-B cells. The Pax5-activated intergenic repeat (PAIR) elements were no longer bound by Pax5 in pre-B and B cells consistent with the loss of antisense transcription, whereas E2A and CTCF interacted with PAIR elements throughout early B-cell development. The pro-B-cell-specific and Pax5-dependent activity of the PAIR elements suggests that they are involved in the regulation of distal VH-DJH recombination at the Igh locus. Analysis of chromatin and TF binding in rag2-/- and pax5-/- rag2-/- pro-B cells. Chip-Chip with one experiment for each antibody, 12 samples.

2011-02-11 | E-GEOD-27074 | biostudies-arrayexpress

IGH analysis in pro-B cells with H3K4me3, H3K4me2, H3K9ac, H3K27me3, Pax5 and CTCF [ChIP-Seq]

Project description:VH-DJH recombination of the immunoglobulin heavy-chain (Igh) locus is temporally and spatially controlled during early B-cell development, and yet no regulatory elements other than the VH gene promoters have been identified throughout the entire 2.5-Mb VH gene cluster. Here we discovered novel regulatory sequences that are interspersed in the distal VH gene region. These conserved repeat elements were characterized by the presence of Pax5-dependent active chromatin, the binding of Pax5, E2A, CTCF and Rad21 as well as by Pax5-dependent antisense transcription in pro-B cells. The Pax5-activated intergenic repeat (PAIR) elements were no longer bound by Pax5 in pre-B and B cells consistent with the loss of antisense transcription, whereas E2A and CTCF interacted with PAIR elements throughout early B-cell development. The pro-B-cell-specific and Pax5-dependent activity of the PAIR elements suggests that they are involved in the regulation of distal VH-DJH recombination at the Igh locus. Analysis of chromatin and TF binding in rag2-/- and wt pro-B, DP T and Mature B cells. Chip-Seq of CTCF and Rad21. The provided data is in mm8 coordinates.

2011-02-11 | E-GEOD-27214 | biostudies-arrayexpress

IGH analysis in pro-B cells with H3K4me3, H3K4me2, H3K9ac, H3K27me3, Pax5 and CTCF [ChIP-Seq]

2011-02-11 | GSE27214 | GEO

IGH analysis in pro-B cells with H3K4me3, H3K4me2, H3K9ac, H3K27me3, Pax5 and CTCF [ChIP-chip]

2011-02-11 | GSE27074 | GEO

EBF1 and PAX5 control pro-B cell expansion via inverse regulation of the c-Myc gene.

Project description:EBF1 and PAX5 are two transcription factors targeted in human B-ALL. Their importance for normal B-cell differentiation has led to the suggestion that impaired function of these proteins contributes to the developmental block observed in B-lineage leukemia. However, increased understanding of the function of these proteins has suggested more complex roles in malignant transformation. We here report that the loss of EBF1 function in B-cell progenitors results in reduced expression of c-MYC. Ectopic expression of c-MYC rescues B-cell expansion in the absence of EBF1 both in vivo and in vitro and ChIP-seq analysis identifies multiple binding sites for EBF1 in putative regulatory elements of the mouse c-Myc gene. On the contrary, expression of PAX5 in EBF1 deficient cells resulted in down regulation of c-Myc and inhibition of cell expansion. Since both EBF1 and PAX5 bind multiple regulatory elements in the c-Myc gene, these data suggest that EBF1 and PAX5 have opposing functions with regard to regulation of c-Myc expression. This suggests the existence of a lineage restricted regulatory loop controlling the expansion of B-lineage progenitors. The binding of EBF1 and PAX5 to multiple regulatory elements in the human c-MYC gene indicate that this regulatory loop may be of relevance for our understanding of leukemia formation.

2019-11-30 | GSE136238 | GEO

EBF1 and PAX5 control pro-B cell expansion via oppose regulation of the Myc gene

Project description:Lineage restricted transcription factors are frequently found mutated in B-lymphoid leukemia, suggesting a close link between normal and malignant B-cell development. One of these transcription factors is EBF1, a protein of critical importance for specification but also survival of B-lymphoid progenitors. We here report that impaired EBF1 function in mouse B-cell progenitors results in reduced expression of Myc. Ectopic expression of MYC rescued B-cell expansion in the absence of EBF1 both in vivo and in vitro. Using chromosome conformation analysis in combination with ATAC, ChIP-seq and reporter gene assays, identified six EBF responsive enhancer elements that could be annotated to the Myc gene. Crispr-Cas9 mediated targeting of EBF1 binding sites identified one element of importance for Myc expression and pro-B cell expansion providing evidence for that Myc is a direct target for EBF1. Furthermore, ChIP-seq analysis suggested that several regulatory elements in the Myc gene were targeted by PAX5. However, ectopic expression of PAX5 in EBF1 deficient cells was found to induce a cell cycle block and reduce Myc expression suggesting that EBF1 and PAX5 act in an opposing manner at this shared target gene. This hypothesis was further substantiated by the finding that Pax5 inactivation reduced the need for EBF1 in pro-B cell expansion. The binding of EBF1 and PAX5 to regulatory elements in the human MYC gene in a B-ALL cell line indicate that this regulatory loop may be of relevance for our understanding of both normal and malignant B-cell development.

2021-03-05 | GSE159957 | GEO

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