SC1/PRDM4 recruits PRMT5 to control the timing of neural precursor differentiation in developing neural stem cells

During cortical development, neural stem cells (NSCs) switch from proliferative to neuron-generating asymmetric divisions. Here we investigated the role of Schwann cell factor 1 (SC1/PRDM4), a transcriptional repressor highly expressed in the developing nervous system, during NSCs development. We found that SC1 protein levels were down-regulated in newly differentiating neurons, while remaining high in undifferentiated NSCs, suggesting an asymmetric inheritance of SC1. Knockdown of SC1 in the NSCs led to precocious differentiation of neurons and its overexpression led to an increase in Nestin-expressing precursors. We found that SC1, through its amino-terminus, recruits the chromatin modifier PRMT5, a histone arginine methyltransferase that catalyses histone H4R3 symmetric dimethylation (H4R3me2s). Mutations disrupting SC1/PRMT5 interaction resulted in loss of SC1-mediated increase in undifferentiated neural precursor cells. Our data demonstrate that SC1 and PRMT5 are components of an epigenetic regulatory complex that provides an epigenetic signature of a “stem-like” cellular state in the NSCs and which may be asymmetrically inherited during neurogenic divisions

The PHD Domain of Np95 (mUHRF1) Is Involved in Large-Scale Reorganization of Pericentromeric Heterochromatin

Heterochromatic chromosomal regions undergo large-scale reorganization and progressively aggregate, forming chromocenters. These are dynamic structures that rapidly adapt to various stimuli that influence gene expression patterns, cell cycle progression, and differentiation. Np95-ICBP90 (m- and h-UHRF1) is a histone-binding protein expressed only in proliferating cells. During pericentromeric heterochromatin (PH) replication, Np95 specifically relocalizes to chromocenters where it highly concentrates in the replication factories that correspond to less compacted DNA. Np95 recruits HDAC and DNMT1 to PH and depletion of Np95 impairs PH replication. Here we show that Np95 causes large-scale modifications of chromocenters independently from the H3:K9 and H4:K20 trimethylation pathways, from the expression levels of HP1, from DNA methylation and from the cell cycle. The PHD domain is essential to induce this effect. The PHD domain is also required in vitro to increase access of a restriction enzyme to DNA packaged into nucleosomal arrays. We propose that the PHD domain of Np95-ICBP90 contributes to the opening and/or stabilization of dense chromocenter structures to support the recruitment of modifying enzymes, like HDAC and DNMT1, required for the replication and formation of PH