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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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			Action	DRS
	SRR12552870.fastq.gz	Fastqsanger.gz
	SRR12552871.fastq.gz	Fastqsanger.gz
	SRR12552872.fastq.gz	Fastqsanger.gz
	SRR12552873.fastq.gz	Fastqsanger.gz
	SRR12552874.fastq.gz	Fastqsanger.gz

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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: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.

| 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

Project description:Drosophila melanogaster Son, Son RNA binding protein, is differentially expressed in 8 experiment(s);

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Son

Project description:Drosophila melanogaster Son, Son RNA binding protein, is expressed in 4 baseline experiment(s);

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Son KD in mouse embryonic stem cells

Project description:Gene-expression noise can influence cell-fate choices across pathology and physiology. However, a crucial question persists: do regulatory proteins or pathways exist that control noise independently of mean expression levels? Resulting from a previous screen, the protein SON was identified as a potential noise regulator. We perform Son KD and utilize single-cell RNA sequencing (scRNA-seq) to quantify the changes in mean/noise of all transcripts. This dataset corresponds to the aforementioned scRNA-seq experiment upon Son KD.

2024-08-05 | GSE270846 | 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

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