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Critical Regulation of a NDIME/Mef2c Axis in Embryonic Stem Cell Neural Differentiation and Autism

ABSTRACT: Recent studies revealed that microdeletion of human chromosome 5q14.3 leads to the occurrence of neurodevelopmental disorders such as autism and intellectual disability, and have identified Mef2c haploinsufficiency as a main cause. Here, we found that a brain-enriched long non-coding RNA, termed NDIME, is located near the Mef2c locus and is required for normal neural differentiation of mouse embryonic stem cells (mESCs). Mechanistic studies showed that exons 1-3 of NDIME interacts with the major component of polycomb repressive complex 2 (PRC2) EZH2, blocking EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) at the Mef2c promoter, ensuring Mef2c transcription. Moreover, both the expression levels of NDIME and Mef2c were significantly downregulated in the hippocampus of autism model mice, while adeno-associated virus (AAV)-mediated expression of NDIME significantly increased the Mef2c expression and ameliorated autism-like behaviors. Collectively, our findings reveal an epigenetic mechanism of NDIME regulating Mef2c transcription and neural differentiation, and the potential effects and application of the NDIME/Mef2c axis in autism.

ORGANISM(S): Mus musculus

PROVIDER: GSE143606 | GEO | 2020/11/03

REPOSITORIES: GEO

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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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Critical Regulation of a NDIME/Mef2c Axis in Embryonic Stem Cell Neural Differentiation and Autism

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