Regulation of lymphoid versus myeloid fate choice by Mef2c
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE13686 | GEO | 2008/11/21
SECONDARY ACCESSION(S): PRJNA110441
REPOSITORIES: GEO
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Project description:Collombet2016 - Lymphoid and myeloid cell
specification and transdifferentiation
This model is described in the article:
Logical modeling of lymphoid
and myeloid cell specification and transdifferentiation
Samuel Collombet, Chris van Oevelen,
Jose Luis Sardina Ortega, Wassim Abou-Jaoudé, Bruno Di
Stefano, Morgane Thomas-Chollier, Thomas Graf, and Denis
Thieffry
Proceedings of the National Academy of
Sciences of the United States of America
Abstract:
Blood cells are derived from a common set of hematopoietic
stem cells, which differentiate into more specific progenitors
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differentiated cells. This developmental process is controlled
by a complex regulatory network involving cytokines and their
receptors, transcription factors, and chromatin remodelers.
Using public data and data from our own molecular genetic
experiments (quantitative PCR, Western blot, EMSA) or
genome-wide assays (RNA-sequencing, ChIP-sequencing), we have
assembled a comprehensive regulatory network encompassing the
main transcription factors and signaling components involved in
myeloid and lymphoid development. Focusing on B-cell and
macrophage development, we defined a qualitative dynamical
model recapitulating cytokine-induced differentiation of common
progenitors, the effect of various reported gene knockdowns,
and the reprogramming of pre-B cells into macrophages induced
by the ectopic expression of specific transcription factors.
The resulting network model can be used as a template for the
integration of new hematopoietic differentiation and
transdifferentiation data to foster our understanding of
lymphoid/myeloid cell-fate decisions.
This model is hosted on
BioModels Database
and identified by:
MODEL1610240000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-06-08 | MODEL1610240000 | BioModels
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Project description:Acute myelogenous leukemia (AML) is driven by leukemic stem cells (LSC) generated by mutations that confer (or maintain) self-renewal potential coupled to an aberrant differentiation program. Using retroviral mutagenesis, we identified genes that generate LSC in collaboration with genetic disruption of the gene encoding interferon response factor 8 (Irf8), which induces a myeloproliferation in vivo. Amongst the targeted genes, we identified Mef2c, encoding a MADS transcription factor, and confirmed that over-expression induced a myelomonocytic leukemia in cooperation with Irf8 deficiency. Strikingly, several of the genes identified in our screen have been reported to be upregulated in the mixed-lineage leukemia (MLL) subtype. High MEF2C expression levels were confirmed in AML patient samples with MLL gene disruptions, prompting an investigation of the causal interplay. Using a conditional mouse strain, we demonstrated that Mef2c deficiency does not impair the establishment nor maintenance of LSC generated in vitro by MLL/ENL fusion proteins â?? however, its loss led to compromised homing and invasiveness of the tumor cells. Mef2c-dependent targets included several genes encoding matrix metalloproteinases and chemokine ligands and receptors, providing a mechanistic link to increased homing and motility. Thus an early event in LSC generation may be responsible for the aggressive nature of this leukemia subtype. Experiment Overall Design: For gene expression profiling of M/E cells, RNA was isolated from M/E-Mef2c del/- cells infected with MYs-iPAC (empty vector) or MYs-pMef2cASR after puromycin selection at three different time points, pooled, and hybridized against the Agilent Whole Mouse Genome Microarray 4x44K using the one-color service of Miltenyi. Transcript levels were verified by real-time RT-PCR using the SYBRGreen Reaction Mix (Roche Mannheim) in a Roche Light-Cycler. cDNA levels were normalized against Hprt transcript levels. Primers and amplification conditions are available upon request.
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