miRNA-132 orchestrates chromatin remodeling and translational control of the circadian clock

Abstract

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.

Involvement of miRNAs in equine follicle development

“…In contrast to PTEN and RASA1, we did not detect any differences in transcript levels of the antiproliferative factor, BTG2, between DO and L follicles. BTG2 is a bonafide target of miR-21 and miR-132 in mouse and human cells respectively (Alvarez-Saavedra et al 2011. Although only limited amounts of granulosa cells could be collected from individual follicles in live mares, which precluded analyses of protein levels in these samples, we cannot exclude a potential miRNA effect on levels of BTG2 protein.…”

Non-coding RNAs as direct and indirect modulators of epigenetic regulation

“…111 miR-132, which is dysregulated in schizophrenia and is involved in antiviral innate immunity and circadian timing, has been to shown regulate gene expression by directly inhibiting DNMT3A, the transcription factor GATA2, EP300 (a transcriptional co-activator), as well as several members of histone modifying complexes in vitro and in vivo. [112][113][114] Endo-siRNAs may also be involved in de novo DNA methylation, as seen with the A. thaliana gene FWA. In this case the process appears to occur in two steps, including initial recruitment of siRNAs to pre-methylated FWA and then either cis-or trans-directed DNA methylation of transgenic copies introduced by transformation with Agrobacterium.…”

Adaptation of molecular circadian clockwork to environmental changes: a role for alternative splicing and miRNAs

“…Thus, miR-132 levels can modulate the negative arm of the circadian clock and the response of the molecular circadian machinery to light. In a follow-up study, Alvarez-Saavedra et al [61] showed that miR-132 controls the molecular clock in response to light by targeting a specific set of chromatin and translational regulators. The chromatin regulator Mecp2 is involved in the expression of the per1 and per2 promoters, and the proteins Btg2 and Paip2a suppress production of PER1 and PER2 by accelerating mRNA decay.…”