Project description:We sorted hematopoietic progenitors from mouse bone marrow previously transplanted with either Csnk1a1 fl/+ or Mx1Cre+ bone marrow and performed scRNAseq. We identified cell populations in a continuum of differentiation from quiescent stem cell to cycling lineage-marker expressing progenitor. Our analysis revealed signaling changes in primitive stem cells with Csnk1a1 haploinsufficiency that result in downregulation of inflammatory NFkB signaling while upregulating Myc and E2f dependent pro-proliferative pathways
Project description:Establishment of a heterozygous genome-wide loss-of-function CRISPR library for studying haploinsufficiency in human embryonic stem cells.
Project description:This SuperSeries is composed of the following subset Series: GSE30537: Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics [mRNA profiling] GSE30538: Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics [ChIP-seq] Refer to individual Series
Project description:We have generated human induced Pluripotent Stem cells (hiPSc) from two individuals with OPA1 haploinsufficiency, and one control donor, using Sendai virus-mediated delivery of reprogramming factors. hiPSc lines have been screened using SNP array to assess chromosomal stability (alongside the fibroblast lines from which they derived), and validation of the pluripotency of the hiPSc lines is provided by Pluritest assessment of transcriptome datasets, prior to differentiation to dopaminergic neuronal clutures and downstream functional assays. Mitochondrial fragmentation in iPSC-derived dopaminergic neurons with OPA1 haploinsufficiency underpins increased apoptosis and syndromic Parkinsonism.
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.