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SON inhibits megakaryocytic differentiation via repressing the megakaryocytic gene expression program in acute megakaryoblastic leukemia

ABSTRACT: SON inhibits megakaryocytic differentiation via repressing the megakaryocytic gene expression program in acute megakaryoblastic leukemia

PROVIDER: PRJNA660403 | ENA |

REPOSITORIES: ENA

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SON inhibits megakaryocytic differentiation via repressing the megakaryocytic gene expression program in acute megakaryoblastic leukemia

Project description:A high incidence of acute megakaryoblastic leukemia (AMKL) in Down syndrome patients implies that chromosome 21 genes have a pivotal role in AMKL development, but the functional contribution of individual genes remains elusive. Here, we report that SON, a chromosome 21-encoded DNA- and RNA-binding protein, inhibits megakaryocytic differentiation by suppressing RUNX1 and the megakaryocytic gene expression program. As megakaryocytic progenitors differentiate, SON expression is drastically reduced, with mature megakaryocytes having the lowest levels. In contrast, AMKL cells express an aberrantly high level of SON, and knockdown of SON induced the onset of megakaryocytic differentiation in AMKL cell lines. Genome-wide transcriptome analyses revealed that SON knockdown turns on the expression of pro-megakaryocytic genes while reducing erythroid gene expression. Mechanistically, SON represses RUNX1 expression by directly binding to the proximal promoter and two enhancer regions, the known +23 kb enhancer and the novel +139 kb enhancer, at the RUNX1 locus to suppress H3K4 methylation. In addition, SON represses the expression of the AP-1 complex subunits JUN, JUNB and FOSB which are required for late megakaryocytic gene expression. Our findings define SON as a negative regulator of RUNX1 and megakaryocytic differentiation, implicating SON overexpression in impaired differentiation during AMKL development.

2020-09-01 | GSE157178 | GEO

SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia.

Project description: Not available

| S-EPMC8155101 | biostudies-literature

MKL1 promotes megakaryocytic differentiation in HEL cells

Project description:Megakaryoblastic Leukemia 1 (MKL1) was identified as part of the t(1;22) translocation specific to acute megakaryoblastic leukemia, but nothing is known regarding its role in hematopoiesis. Here we show that overexpression of MKL1 enhances megakaryocytic differentiation of the Human Erythroleukemia cell line (HEL). Microarray analysis reveals that MKL1 promotes expression of megakaryocyte-specific genes such as glycoprotein V (GP5), as well as cytoskeletal and adhesion molecule genes relevant to megakaryocyte differentiation and proplatelet formation. MKL1 is a transcriptional coactivator of Serum Response Factor. In this study, MKL1 also upregulates known SRF targets. Results provide insight into the role of MKL1 in megakaryocytopoiesis.

2008-12-10 | GSE13710 | GEO

SON and its alternatively spliced isoforms control MLL complex-mediated H3K4me3 and transcription of leukemia-associated genes (ChIP-seq data)

Project description:Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy, but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia.

2016-03-24 | GSE76910 | GEO

Son Maintains Accurate Splicing of Pre-mRNAs Encoding Chromatin Modifiers

Project description:Exon and expression analysis of HeLa cells after knockdown of SON Serine-arginine-rich (SR) proteins play a key role in alternative pre-mRNA splicing in eukaryotes. Our laboratory recently showed that a large SR protein called Son has unique repeat motifs that are essential for maintaining the subnuclear organization of pre-mRNA processing factors in nuclear speckles. Motif analysis of Son highlights putative RNA interaction domains that suggest a direct role for Son in pre-mRNA splicing. A genome-wide screen was performed to identify putative human transcription and splicing targets of Son.

2011-12-22 | GSE28672 | GEO

Son Maintains Accurate Splicing of Pre-mRNAs Encoding Chromatin Modifiers

2011-12-22 | E-GEOD-28672 | biostudies-arrayexpress

Chidamide inhibits double expressor lymphoma through repressing Myc expression and activity

Project description:Chidamide inhibits double expressor lymphoma through repressing Myc expression and activity

| PRJNA725123 | ENA

Expression data from HeLa cells transiently transfected with control siRNA or SON siRNA

2011-04-01 | GSE26888 | GEO

RNA-Seq after knockdown of SON in human embryonic stem cells

Project description:Human embryonic stem cells (hESCs) harbor the ability to undergo lineage-specific differentiation into clinically relevant cell types. Transcription factors and epigenetic modifiers are known to play important roles in the maintenance of pluripotency of hESCs. However, little is known about regulation of pluripotency through splicing. In this study, we identify the spliceosome-associated factor SON as a novel factor essential for the maintenance of hESCs. Depletion of SON in hESCs results in the loss of pluripotency and cell death. Using genome-wide RNA profiling, we identified transcripts that are regulated by SON. Importantly, we confirmed that SON regulates the proper splicing of transcripts encoding for pluripotency regulators such as PRDM14, OCT4, E4F1 and MED24. Furthermore, we show that SON is bound to these transcripts in vivo. In summary, we connect a splicing-regulatory network for accurate transcription production to the maintenance of pluripotency and self-renewal of hESCs.

2013-08-29 | E-MTAB-1687 | biostudies-arrayexpress

Expression data from HeLa cells transiently transfected with control siRNA or SON siRNA

Project description:SON is a large Ser/Arg (SR)-related protein localized in nuclear speckles. SON siRNA causes defects in mitotic progression and genome instability. We used microarrays to detail the pattern of gene expression after SON knockdown. HeLa cells were grown in 100 mm dishes and transfected with negative control siRNA or SON siRNA (400 pmol). Then, cells were harvested after 66 hours and RNAs were isolated. Microarrays were performed using GeneChip Human Genome U133A 2.0 (Affymetrix).

2011-04-01 | E-GEOD-26888 | biostudies-arrayexpress

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