Mammalian circadian rhythms are synchronized to the external time by daily resetting of the suprachiasmatic nucleus (SCN) in response to light. As the master circadian pacemaker, the SCN coordinates the timing of diverse cellular oscillators in multiple tissues. Aberrant regulation of clock timing is linked to numerous human conditions, including cancer, cardiovascular disease, obesity, various neurological disorders and the hereditary disorder familial advanced sleep phase syndrome. Additionally, mechanisms that underlie clock resetting factor into the sleep and physiological disturbances experienced by night-shift workers and travelers with jet lag. The Ca(2+)/cAMP response element-binding protein-regulated microRNA, miR-132, is induced by light within the SCN and attenuates its capacity to reset, or entrain, the clock. However, the specific targets that are regulated by miR-132 and underlie its effects on clock entrainment remained elusive until now. Here, we show that genes involved in chromatin remodeling (Mecp2, Ep300, Jarid1a) and translational control (Btg2, Paip2a) are direct targets of miR-132 in the mouse SCN. Coordinated regulation of these targets underlies miR-132-dependent modulation of Period gene expression and clock entrainment: the mPer1 and mPer2 promoters are bound to and transcriptionally activated by MeCP2, whereas PAIP2A and BTG2 suppress the translation of the PERIOD proteins by enhancing mRNA decay. We propose that miR-132 is selectively enriched for chromatin- and translation-associated target genes and is an orchestrator of chromatin remodeling and protein translation within the SCN clock, thereby fine-tuning clock entrainment. These findings will further our understanding of mechanisms governing clock entrainment and its involvement in human diseases.

Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.

SUMMARY Balancing progenitor cell self-renewal and differentiation is essential for brain development and is regulated by the activity of chromatin remodeling complexes. Nevertheless, linking chromatin changes to specific pathways that control cortical histogenesis remains a challenge. Here we identify a genetic interaction between the chromatin remodeler Snf2l and Foxg1, a key regulator of neurogenesis. Snf2l mutant mice exhibit forebrain hypercellularity arising from increased Foxg1 expression, increased progenitor cell expansion, and delayed differentiation. We demonstrate that Snf2l binds to the Foxg1 locus at midneurogenesis and that the phenotype is rescued by reducing Foxg1 dosage, thus revealing that Snf2l and Foxg1 function antagonistically to regulate brain size.