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Ybx1 negatively regulates PRC2 to affect gene expression programs for neural lineage specification and neural progenitor self-renewal and differentiation [ChIP-seq]

ABSTRACT: Chromatin modifiers affect the spatiotemporal expression of gene expression programs that underlie organismal development. The Polycomb repressive complex 2 (PRC2) has emerged as a crucial player in executing neurodevelopmental programs. Here we show that the nucleic acid–binding protein Ybx1 interacts with PRC2 in human and mouse neural progenitor cells (NPCs). During early neural development in vivo, Ybx1 is required for forebrain specification and modulates mid/hindbrain growth. In NPCs, Ybx1 controls the self-renewal and neuronal differentiation. Mechanistically, Ybx1 binds PRC2 gene targets, reduces the levels of PRC2-mediated H3K27me3, and promotes the expression of genes in forebrain specification, cell proliferation, or neuronal differentiation. In Ybx1-knockout NPCs, H3K27me3 reduction by PRC2 enzymatic inhibitor or genetic depletion partially rescues the control of gene expression, self-renewal, and neuronal differentiation. Our findings suggest that Ybx1 modulates H3K27me3 by PRC2 to regulate spatiotemporal gene expression in embryonic neural development and uncover a crucial epigenetic mechanism balancing forebrain–hindbrain lineages and selfrenewal-differentiation choices in NPCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE137778 | GEO | 2020/06/16

REPOSITORIES: GEO

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Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the âageâ of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SZ might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SZ hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes and WNT signaling. Methods: We compared global transcription of forebrain NPCs from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC NPC samples; 848 genes were significantly differentially expressed (FDR<0.01) Conclusions: The WNT signaling pathway was enriched 2-fold (fisher exact test p-value = 0.031). 1-2 independent differentiations (biological replicates) for each of four control and four schizophrenia patients were analyzed; samples were generated in parallel to neuron RNAseq data.

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Ybx1 negatively regulates PRC2 to affect gene expression programs for neural lineage specification and neural progenitor self-renewal and differentiation [ChIP-seq]

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