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Next Generation Sequencing of mouse hematopoietic cells retrovirally transfected with MNX1 or empty vector (Ctr) from fetal liver or mouse bone marrow and treated with or without pan-inhibitor against SAM-dependent methyltransferases Sinefungin

ABSTRACT: Acute myeloid leukemia (AML) results from aberrant hematopoietic processes and these changes are frequently initiated by chromosomal translocations. One particular subtype, AML with translocation t(7;12)(q36;p13), is found in children diagnosed before two years of age. The chromosomal breakage points of the t(7;12) have consistently been found to be located after exon 1 in the Motor neuron and pancreas homeobox 1 (MNX1) gene in chromosome 7, and after exon 2 in the ETV6 gene in chromosome 12. The aim of this study is the investigation of the leukomogenic potenial of MNX1 overexpression and MNX1-ETV6 fusion using mouse models, in addition to the molecular pathway through which MNX1 is inducing leukemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE202137 | GEO | 2022/06/14

REPOSITORIES: GEO

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Project description:Motor neuron (MN), together with interneuron, are the two major neuronal types in spinal cord. MNs control muscle movement and are essential for breathing, walking and fine motor skills. Malfunction of MNs is frequently associated with neuronal diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. To establish normal function, MNs need to be differentiated properly from neural progenitor cells. Thus, it is of great importance to study the mechanism for MN specification. This study focuses on Mnx1 - a conserved homeobox transcription factor gets expressed during MN specification. Mnx1 is also the most widely used MN marker. Previous studies reported that Mnx1 mutation in mouse causes early lethality - probably by affecting the controlling over respiratory system. However, the exact role of Mnx1 for MN identity remains poorly understood. Taking advantage of a recently developed in vitro model for efficient MN induction from mouse ES cells, we combined experimental and OMICs techniques to systematically investigate the molecular function of Mnx1. We identified thousands of Mnx1 binding sites - many are co-bound by core MN factor Lhx3 and Isl1 and lack active histone marks. Disruption of Mnx1 causes increased expression of 85 genes - while only 14 genes get down-regulated. Up-regulated genes are enriched with neuronal functions, usually get expressed during MN differentiation, and tend to have higher expression in motor neurons and brain compared with other tissues – indicating Mnx1 may fine tune neuronal genes to desired level. However, only a dozen of regions with increased H3K27ac marks are bound by Mnx1, and only two up-regulated genes (Pbx3 and Pou6f2) are identified as putative direct targets of Mnx1 - both are core neuronal factors with the potential to regulate other differential neuronal genes. These results suggest that Mnx1 may contribute to MN identity by fine-tuning the expression of many neuronal genes through direct regulation of a few core neuronal transcription factors. In summary, this study represents the first systematic investigation about the molecular function of the core MN factor Mnx1. It clarifies the mechanism of Mnx1 for MN identity, and also improves the understanding about the regulation mode of homeobox transcription factors.

Dataset Information

Next Generation Sequencing of mouse hematopoietic cells retrovirally transfected with MNX1 or empty vector (Ctr) from fetal liver or mouse bone marrow and treated with or without pan-inhibitor against SAM-dependent methyltransferases Sinefungin

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