Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

SETD5-coordinated chromatin reprogramming regulates adaptive resistance to targeted pancreatic cancer therapy

ABSTRACT: SETD5-coordinated chromatin reprogramming regulates adaptive resistance to targeted pancreatic cancer therapy

PROVIDER: PRJNA595697 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR10693388_1.fastq.gz	Fastqsanger.gz
	SRR10693388_2.fastq.gz	Fastqsanger.gz
	SRR10693389_1.fastq.gz	Fastqsanger.gz
	SRR10693389_2.fastq.gz	Fastqsanger.gz
	SRR10693390_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 24

Similar Datasets

SETD5-coordinated chromatin reprogramming regulates adaptive resistance to targeted pancreatic cancer therapy

Project description:Oncogenic KRAS signaling is a hallmark of pancreatic ductal adenocarcinoma (PDAC), a lethal malignancy with few treatment options. A major roadblock in deploying therapies targeting the KRAS-MAPK pathway is the rapid emergence of resistant cancer cells. However, molecular mechanisms underlying adaptive targeted therapy resistance in PDAC are poorly understood. Here we find SETD5 (SET domain containing 5) as a major epigenetic driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is identified in a genetic screen of annotated methyltransferases that mediate MEKi toxicity in PDAC cells. SETD5 expression is induced upon PDAC cells and tumors acquring MEKi-resistance and SETD5 deletion restores vulnerability of refractory PDAC to MEKi therapy in mouse models and patient-derived xenografts (PDX). SETD5 lacks intrinsic histone methyltransferase activity and rather scaffolds a distinct corepressor complex that regulates HDAC3 and G9a catalytic behaviors to couple selective deacetylation with methylation of histone H3 at lysine 9 (H3K9). Gene silencing by the SETD5 complex regulates a network of known drug resistance pathways to reprogram cellular responses to MEKi, a resistance program disrupted by G9a and HDAC3 blockade. Combinatorial pharmacological targeting of MEK1/2, G9a, and HDAC3 results in sustained tumor growth inhibition in murine and human models of PDAC. Together, our work uncovers SETD5 as a master epigenetic regulator of acquired MAPK-pathway therapy resistance and suggests an efficacious clinical path for MEKi in PDAC.

2020-05-06 | GSE142046 | GEO

SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.

Project description:Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.

| S-EPMC8187079 | biostudies-literature

Transcriptional profiling of Setd5 heterozygous and knockout mouse embryonic stem cells

Project description:SET-domain containing proteins play a vital role in regulating gene expression during development through modifications in chromatin structure. To study molecular function of SET domain containing 5 (Setd5), we assessed global changes in the mouse embryonic stem cell transcriptome when Setd5 gene is knocked out.

2016-12-13 | E-MTAB-5189 | biostudies-arrayexpress

Expression data from SETD5-expressing 3T3-L1 cells.

Project description:SETD5 target genes in 3T3-L1 cells were analyzed.

2021-10-25 | GSE183845 | GEO

SETD5 haploinsufficiency affects mitochondrial compartment in neural cells

Project description:Neurodevelopmental disorders (NDDs) are heterogeneous conditions due to alterations of a variety of molecular mechanisms and cell dysfunctions. Epigenetic basis of NDDs have been reported in an increasingly number of cases while mitochondrial dysfunctions are more common within NDD patients than in the general population. Here, we investigated experimental models of Setd5 haploinsufficiency, that leads to NDDs in humans due to chromatin defects, and uncovered that mitochondrial dysfunction participates in the pathogenesis. Mitochondrial impairment is facilitated by transcriptional aberrations that follow the decrease of SETD5 enzyme. Low levels of SETD5 resulted in fragmented mitochondria, less mitochondrial potential and ATP production both in neural precursors and neurons. Mitochondria were miss-localized in mutant neurons, with few organelles within neurites and synapses. Our study explores the epigenetics/mitochondria interplay as an important aspect of NDD pathophysiology and defines the impairments of mitochondrial functionality and dynamics as new therapeutic targets for disorders associated with loss of SETD5.

2023-01-05 | GSE222188 | GEO

ChIP-sequence analysis of H3K27ac, H3K4me1, and SETD5 in 3T3-L1 preadipocytes.

Project description:Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.

2021-10-25 | GSE183846 | GEO

Haploinsufficiency of the intellectual disability-gene SETD5 disturbs developmental gene expression and cognition

Project description:SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5 haploinsufficient mice present developmental defects such as abnormal brain to body weight ratio and neural crest defect associated phenotypes. Furthermore, Setd5 mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalisation and behavioural inflexibility. Behavioural issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data suggest that Setd5 might regulate RNA polymerase II dynamics and gene transcription during development and learning via its interaction with the Hdac3 and Paf1 complexes. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in intellectual disability and autism spectrum disorder patients.

2018-11-05 | GSE119498 | GEO

SETD5 is a H3K36 methyltransferase which preserves transcriptional fidelity during brain development and neuronal wiring [ChIP-seq]

Project description:We assess the epigenetic function of Setd5 in mouse neural stem cells (NSCs), by profiling a panel of histone modifications and Setd5 binding in wild type and Setd5 heterozygous NSCs.

2019-07-10 | GSE104274 | GEO

Next generation sequencing in SETD5-depleted Huh7 cells.

Project description:To analyze transcriptomic changes in SETD5-deficient Huh7 cells, we performed RNA-sequencing.

2022-09-15 | GSE193431 | GEO

Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice [bulk RNA]

Project description:SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multi electrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5+/- cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5+/- animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.

2018-10-10 | GSE121099 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data