Analysis of gene expression in Idasanutlin-arrested SIN3A and SIN3B depleated cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1005179 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25628718_1.fastq.gz | Fastqsanger.gz | |||
| SRR25628718_2.fastq.gz | Fastqsanger.gz | |||
| SRR25628719_1.fastq.gz | Fastqsanger.gz | |||
| SRR25628719_2.fastq.gz | Fastqsanger.gz | |||
| SRR25628720_1.fastq.gz | Fastqsanger.gz |
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Project description:mRNA expression analysis of arrested HCT116 cells (wild-type or SIN3B-/-) transfected with either non-targeting control siRNA or one of three SIN3A siRNAs and treated with Idasanulin to activate p53.
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Project description:Sin3A and Sin3B bind to distinct and overlapping target sites. Sin3 proteins bind to distinct sites in cycling myoblasts whereas there is a converge of Sin3A and Sin3B proteins to sites in differentiated myotubes. We identified a subset of Sin3 target genes involved in muscle differentiation and physiology and showed that conditional ablation of Sin3 proteins in vivo in mouse results in sarcomere defects Examination of Sin3A and Sin3B binding during myogenesis
2011-01-01 | E-GEOD-22554 | biostudies-arrayexpress
Project description:Sin3A and Sin3B bind to distinct and overlapping target sites. Sin3 proteins bind to distinct sites in cycling myoblasts whereas there is a converge of Sin3A and Sin3B proteins to sites in differentiated myotubes. We identified a subset of Sin3 target genes involved in muscle differentiation and physiology and showed that conditional ablation of Sin3 proteins in vivo in mouse results in sarcomere defects
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Project description:Transcription products influenced by decreased SIN3A or SIN3B are analyzed and compared.
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Project description:Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ~230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.
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Project description:Targeting MDM2 is an attractive therapeutic approach for TP53 wild-type (WT) tumors, including the majority of de novo acute myeloid leukemia (AML) cases. However, patients with WT TP53 have shown variable responses to MDM2 inhibitors in clinical trials, highlighting the need to identify additional biomarkers to maximize the chances of clinical success. We performed CRISPR-Cas9 knockout screens to identify genes that confer resistance to an MDM2 inhibitor idasanutlin. We did not find recurrent sgRNA hits or mutations in p53 downstream targets, such as CDKN1A, BAX, PMIAP1, and BBC3, apart from TP53. This was consistent with the results of individual knockout validation experiments and exome sequencing data from idasanutlin resistant cell lines generated form long-term exposure to low doses of idasanutlin. RNA-seq differential expression analysis revealed that major p53 downstream targets were upregulated in both idasanutlin-sensitive MOLM13 and resistant OCIAML3 cell lines after idasanutlin treatment. These findings highlight the pleiotropic functions of TP53 and suggest that the loss of individual downstream targets of TP53 does not significantly contribute to MDM2 inhibitor resistance.
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Project description:SIN3 corepressor complexes play important roles in both normal development and breast cancer. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions in many developmental processes. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. We generated stable knockdown cells of SIN3 paralogs individually and in combination using three non-overlapping shRNA. Stable knockdown of SIN3B caused a significant decrease in transwell invasion through Matrigel and decreased the number of invasive colonies when grown in a 3D extracellular matrix. Conversely, stable knockdown of SIN3A significantly increased transwell invasion and increased the number of invasive colonies. These results were corroborated in vivo in which SIN3B knockdown significantly decreased and SIN3A knockdown increased experimental lung metastases. RNA sequencing was used to identify unique targets and biological pathways that were altered upon knockdown of SIN3A compared to SIN3B. Additionally, we analyzed microarray data sets to identify correlations of SIN3A and SIN3B expression with survival in patients with breast cancer. These data sets indicated that high mRNA expression of SIN3A as well as low mRNA expression of SIN3B correlates with longer relapse free survival specifically in patients with triple negative breast cancer which corresponds with our in vitro and in vivo data. These results demonstrate key functional differences between SIN3 paralogs in regulating the process of breast cancer metastasis and suggest metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B.
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Project description:Targeting MDM2 is an attractive therapeutic approach for TP53 wild-type (WT) tumors, including the majority of de novo acute myeloid leukemia (AML) cases. However, patients with WT TP53 have shown variable responses to MDM2 inhibitors in clinical trials, highlighting the need to identify additional biomarkers to maximize the chances of clinical success. We performed CRISPR-Cas9 knockout screens to identify genes that confer resistance to an MDM2 inhibitor idasanutlin. We did not find recurrent sgRNA hits or mutations in p53 downstream targets, such as CDKN1A, BAX, PMIAP1, and BBC3, apart from TP53. This was consistent with the results of individual knockout validation experiments and exome sequencing data from idasanutlin resistant cell lines generated form long-term exposure to low doses of idasanutlin. RNA-seq differential expression analysis revealed that major p53 downstream targets were upregulated in both idasanutlin-sensitive MOLM13 and resistant OCIAML3 cell lines after idasanutlin treatment. These findings highlight the pleiotropic functions of TP53 and suggest that the loss of individual downstream targets of TP53 does not significantly contribute to MDM2 inhibitor resistance.
2024-08-15 | GSE240977 | GEO
Project description:Sin3a is the central scaffold protein of the prototypical Hdac1/2 chromatin repressor complex, crucially required during early embryonic development for the growth of pluripotent cells of the inner cell mass. Here, we explore the endogenous composition of the Sin3a-Hdac complex in pluripotent embryonic stem (ES) and differentiated cells. To do this, we established an endogenous double immunoprecipitation strategy coupled with quantitative mass spectrometry (ENDIP-MS) allowing us to define the precise composition of the Sin3a complex in multiple cell types. We identify the Fam60a subunit as a key defining feature of a variant Sin3a complex present in ES cells, but not in differentiated cells. Fam60a co-occupies H3K4me3 positive promoters with Sin3a and is essential to maintain it on chromatin. Consistent with this, Fam60a depletion phenocopies the loss of Sin3a, leading to decreased proliferation, an extended G1-phase and the deregulation of genes associated with differentiation. Taken together, our data characterise Fam60a as an essential core subunit of a variant Sin3a complex in ES cells required to promote rapid proliferation and to prevent unscheduled differentiation.
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Project description:We report differences in gene expression between WT and Sin3B KO HSCs.
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