Dataset Information

Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response

ABSTRACT: The study deals with the elucidation of potential interaction partners of the intracellular domain of the transmembrane receptor Notch1, termed NICD. The NICD is released from the cytoplasmic tail of the Notch receptor by gamma-secretase treatment and translocated as a transcription factor to the nucleus. Here, virally transduced recombinant NICD constructs (wild-type and deltaEP hyperactive mutant) were employed for AP-MS with the aim of identifying novel NICD interactors in a murine T cell leukemia cell line.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): T Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Gerhard Mittler

LAB HEAD: Gerhard Mittler

PROVIDER: PXD008747 | Pride | 2018-06-25

REPOSITORIES: Pride

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Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response.

Giaimo Benedetto Daniele BD Ferrante Francesca F Vallejo Diana M DM Hein Kerstin K Gutierrez-Perez Irene I Nist Andrea A Stiewe Thorsten T Mittler Gerhard G Herold Susanne S Zimmermann Tobias T Bartkuhn Marek M Schwarz Peggy P Oswald Franz F Dominguez Maria M Borggrefe Tilman T

Nucleic acids research 20180901 16

A fundamental as yet incompletely understood feature of Notch signal transduction is a transcriptional shift from repression to activation that depends on chromatin regulation mediated by transcription factor RBP-J and associated cofactors. Incorporation of histone variants alter the functional properties of chromatin and are implicated in the regulation of gene expression. Here, we show that depletion of histone variant H2A.Z leads to upregulation of canonical Notch target genes and that the H2 ...[more]

PMID: 29986055

Similar Datasets

Project description:Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL. Experiment Overall Design: Duplicate samples (biologic replicas) from CUTLL1 cells were treated for 24 hours with vehicle only (DMSO), dexamethasone (1microM), a gamma-secretase inhibitor (CompE 100nM) and a combination of dexamethasome plus gamma secretase inhibitor at the same concentrations indicated before. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (CompE) or the combination of both treatments.

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	BekoBioNICDdEP_01.raw	Raw
	BekoBioNICDdEP_02.raw	Raw
	BekoBioNICDdEP_03.raw	Raw
	BekoBirA_01.raw	Raw
	BekoBirA_02.raw	Raw