BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA999672 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25451851_1.fastq.gz | Fastqsanger.gz | |||
| SRR25451851_2.fastq.gz | Fastqsanger.gz | |||
| SRR25451852_1.fastq.gz | Fastqsanger.gz | |||
| SRR25451852_2.fastq.gz | Fastqsanger.gz | |||
| SRR25451853_1.fastq.gz | Fastqsanger.gz |
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Project description:Scn2a deletion disrupts oligodendroglia function: Implication for myelination, neural circuitry, and auditory hypersensitivity in ASD.
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Project description:Skeletal mandibular hypoplasia (SMH), one of the common types of craniofacial deformities, seriously affects appearance, chewing, pronunciation, and breathing. Moreover, SMH is prone to inducing obstructive sleep apnea syndrome. We found that brain and muscle ARNT-like 1 (BMAL1), the core component of the molecular circadian oscillator, was significantly decreased in mandibles of juvenile SMH patients. Accordingly, SMH was observed in circadian rhythm-disrupted or BMAL1-deficiency mice. RNA sequencing and protein chip analyses suggested that matrix metallopeptidase 3 (MMP3) is the potential target of BMAL1 during the mandibular developmental process. Interestingly, in juvenile SMH patients, we observed that MMP3 level was increased obviously. Consistently, MMP3 was upregulated during the whole growth period of 3 to 10 weeks in Bmal1-/- mice. Given these findings, we set to characterize the underlying mechanism and found that BMAL1-deficiency enhanced Mmp3 transcription through activating p65 phosphorylation. Together our results provide new insight into the mechanism by which BMAL1 is implicated in the pathogenesis of SMH
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Project description:Sleep is regulated by intricate homeostatic and circadian systems and is influenced by genetic, environmental, and lifestyle factors. However, the roles of the epitranscriptome in sleep-wake regulation remain to be clarified. Here, we find that mice lacking the rRNA methyltransferase Nsun5 exhibit prolonged wakefulness. The absence of Nsun5 decreases 28S rRNA m5C levels, impairing the translational efficiency of nascent proteins associated with myelination, microtubule-based movement, and ribosome binding. This leads to a decreased number of oligodendrocytes and hypomyelination. These deficits result in increased excitability, particularly within the cortex. Notably, restoring myelination properties with clemastine or blocking the abnormally exposed voltage-gated potassium channels rescues the sleep phenotype, suggesting that reduced sleep is associated with hypomyelination. These findings highlight the significant role of epigenetic modifications in sleep regulation and offer broad mechanistic and therapeutic implications for brain disorders involving both myelin and sleep disturbances.
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Project description:TMT analysis of proteomic changes in the gastrocnemius skeletal muscles of WT and Bmal1-KO mice, and Bmal1-KO mice rescued with AAV-mediated muscle-specific expression of Bmal1.
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Project description:Autism spectrum disorder (ASD) is characterized by a complex etiology, with genetic determinants significantly influencing its manifestation. Among these, the Scn2a gene emerges as a pivotal player, crucially involved in oligodendrocyte (OL) function. The present study elucidates the underexplored roles of Scn2a in OL functionality, subsequently affecting myelination and auditory neural processes. The results reveal a nuanced interplay between OLs and axons, where Scn2a deletion causes alterations in OL differentiation and myelination. This disruption, in turn, instigates changes in axonal properties and neuronal activities at the single cell level. Furthermore, OL-specific Scn2a deletion compromises the integrity of neural circuitry within auditory pathways, leading to auditory hypersensitivity—a common sensory abnormality observed in ASD. Through transcriptional profiling, we identified alterations in the expression of myelin-associated genes, highlighting the cellular consequences engendered by Scn2a deletion. In summary, the findings of this study provide unprecedented insights into the pathway from Scn2a deletion in OL to sensory abnormalities in ASD, underscoring the integral role of Scn2a-mediated OL myelination in auditory responses. This research thereby provides novel insights into the intricate tapestry of genetic and cellular interactions inherent in ASD.
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Project description:To define regulation of tissue proteomes by Bmal1, daily feeding rhythm, and the interaction, we employed Bmal1-stopFL mice, which do not express the main transcriptional activator of the molecular clock, Bmal1, except in cre recombinase-expressing cells1,2 (Figure 1A). Bmal1-stopFL mice lacking cre (Bmal1 knockout, KO) are analogous to Bmal1-null mice and display severely impaired behavioral and molecular rhythms1-3. Hepatocyte-specific Alfp-cre and skeletal muscle-specific Hsa-cre genes were introduced to generate a single line wherein both hepatocyte and skeletal muscle Bmal1 were reconstituted (Liver+Muscle-RE), i.e., rescued (Smith, Koronowski et al. 2023). This approach had the benefit of analyzing liver and muscle from the same mice but comes with the qualification that the abundance of some proteins may be influenced by Bmal1 function in the other tissue, or by a synergistic effect of Bmal1 in both tissues, rather than through rescue of local Bmal1 function alone. Proteomic anlaysis was performed in liver and skeletal muscle.
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Project description:Advances in circadian research revealed an intricate relationship between aging and circadian rhythms. However, whether and how the circadian machinery contribute to stem cell aging, especially in primates, remains poorly understood. In this study, we investigated the role of BMAL1, the only non-redundant circadian clock component, during aging in mesenchymal progenitor cells (MPCs). We observed an accelerated aging phenotype in both BMAL1 deficient human and cynomolgus monkey MPCs. Notably, this phenotype is mainly attributed to a transcriptional-independent role of BMAL1 in stabilizing the heterochromatin and thus preventing LINE1 activation. In senescent MPCs from human and cynomolgus monkeys, dampened LINE1 binding capacity of BMAL1 and synergistically activated LINE1 transcripts were observed. Furthermore, similar de-stabilized heterochromatin and aberrant LINE1s transcription was observed in the skin and muscle tissues from BMAL1-deficient cynomolgus monkey. Altogether, these findings uncover a noncanonical role of BMAL1 in stabilizing heterochromatin to inactivate LINE1 that drives aging in primates.
2022-03-18 | PXD030570 | Pride
Project description:Although circadian and sleep disorders are frequently associated with autism spectrum disorders (ASD), it remains elusive whether clock gene disruption can lead to autistic-like phenotypes in animals. The essential clock gene Bmal1 has been associated with human sociability and its missense mutations are identified in ASD. Here we report that global Bmal1 deletion led to significant social impairments, excessive stereotyped and repetitive behaviors, as well as motor learning disabilities in mice, all of which resemble core behavioral deficits in ASD. Furthermore, aberrant cell density and immature morphology of dendritic spines were identified in the cerebellar Purkinje cells (PCs) of Bmal1 knockout (KO) mice. Electrophysiological recordings uncovered enhanced excitatory and inhibitory synaptic transmission and reduced firing rates in the PCs of Bmal1 KO mice. Differential expression of ASD- and ataxia-associated genes (Ntng2, Mfrp, Nr4a2, Thbs1, Atxn1, and Atxn3) and dysregulated pathways of translational control, including hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling, were identified in the cerebellum of Bmal1 KO mice. Interestingly, the antidiabetic drug metformin reversed mTORC1 hyperactivation and alleviated major behavioral and PC deficits in Bmal1 KO mice. Importantly, conditional Bmal1 deletion only in cerebellar PCs was sufficient to recapitulate autistic-like behavioral and cellular changes akin to those identified in Bmal1 KO mice. Together, these results unveil a previously unidentified role for Bmal1 disruption in cerebellar dysfunction and autistic-like behaviors. Our findings provide experimental evidence supporting a putative role for dysregulation of circadian clock gene expression in the pathogenesis of ASD.
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