Biology subjects

Zhou, F.-Q.

Publications and source records attributed to Zhou, F.-Q..

9 recordsLinked to original sources

bioRxiv2023

X chromosome encoded histone demethylase UTX regulates mammalian axon regeneration via microRNA-124

Epigenetic regulation of neuronal transcriptomic landscape is emerging to be a key coordinator of mammalian neural regeneration. Here we investigated roles of two histone 3 lysine 27 (H3K27) demethylases Kdm6a/b in controlling neuroprotection and axon regeneration. Deleting either Kdm6a or Kdm6b led to enhanced sensory axon regeneration in the PNS, whereas in the CNS only deleting Kdm6a in retinal ganglion cells (RGCs) significantly enhanced optic nerve regeneration. Moreover, both Kdm6a and Kdm6b functioned to regulate RGC survival but with different mechanisms. Mechanistically, Kdm6a regulates RGC regeneration via distinct pathway from that of Pten and co-deleting Kdm6a and Pten resulted in long distance optic nerve regeneration passing the optic chiasm. In addition, RNA-seq profiling revealed that Kdm6a deletion switched the RGC transcriptomics into a developmental-like state and suppressed several known repressors of neural regeneration. Klf4 was identified as a direct downstream target of Kdm6a-H3K27me3 signaling in both sensory neurons and RGCs to regulate axon regeneration. These findings not only revealed different roles of Kdm6a and Kdm6b in regulation of neural regeneration and their underlying mechanisms, but also identified Kdm6a- mediated histone demethylation signaling as a novel epigenetic target for supporting CNS neural regeneration.

neuroscience↗

bioRxiv2023

Targeting pioneer transcription factor Ascl1 to promote optic nerve regeneration

In adult mammalian central nervous system (CNS) neurons, axon regeneration after injury remains limited due to unfavorable gene regulatory programs. Factors enabling comprehensive epigenetic and transcriptional transitions, for instance, pivotal transcription factors that mediate neurogenesis and morphogenesis may be sufficient to promote CNS axon regeneration. Based on the analyses of multiple public whole-genome RNA and chromatin accessibility sequencing dataset of mouse retina development, as well as previous functional studies on the regeneration-capable dorsal root ganglion neurons, we hypothesize that the overexpression of pioneer transcription factor Achaete-Scute homolog 1 (Ascl1) would promote axon regeneration in the adult mammalian CNS neurons. We employed the optic nerve crush in mice, a common model for studying CNS axon regeneration, neuron survival and glaucoma, to investigate the effect of Ascl1 overexpression on the post-injury optic nerve regeneration. We found that Ascl1 could sufficiently promote regenerated axons past the crush site and significantly preserve the survival of retinal ganglion cells. Mechanistically, we revealed that effects of Ascl1 was mediated by known pro-regeneration factor Sox11 but not others. Together, our study established an effective workflow combined with the integrated computational inference and experimental validation for discovering functionally important target for promoting CNS neuron axon regeneration and survival.

neuroscience↗

bioRxiv2022

Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via epigenetic regulation of key regenerative pathways

Current clinical treatment for neurodegenerative diseases and neural injuries falls short of success, and one primary reason is that neurons in the mammalian central nervous system (CNS) lose their regeneration ability as they mature. Previous studies indicated that the regeneration ability of neurons is governed by complex signaling networks involving many genes. Therefore, here we investigated the roles of Ezh2, a histone methyltransferase, in regulation of mammalian axon regeneration at the epigenetic level. We found that Ezh2 level was gradually downregulated in the mouse nervous system during maturation but significantly upregulated in mature sensory neurons during spontaneous axon regeneration in the peripheral nerve system (PNS), suggesting its role in supporting axon regeneration. Indeed, Ezh2 loss-of-function in sensory neurons impaired PNS axon regeneration in vitro and in vivo. In contrast, overexpression of Ezh2 in retinal ganglion cells in the CNS induced optic nerve regeneration after optic nerve injury in both methyltransferase-dependent and -independent manners. Mechanistic exploration with multiomics sequencing, together with functional analyses, revealed that Ezh2 supported axon regeneration by systematically silencing the transcription of genes regulating synaptic function and axon regeneration inhibitory signaling, while broadly activating factors promoting axon regeneration. Our study not only reveals that Ezh2 coordinates axon regeneration via epigenetically regulating multiple key regenerative pathways, but also suggests that modulating chromatin accessibility is a promising strategy to promote CNS axon regeneration.

neuroscience↗

bioRxiv2021

UCHL1 inhibited by A1 astrocytes facilitates aggregates clearance to promote neural stem cells activation after spinal cord injury

Activation of endogenous neural stem cells (NSCs) is critically important for the adult neurogenesis. However, NSC activation is extremely limited after spinal cord injury (SCI). Recent evidence suggests that accumulation of protein aggregates impedes quiescent NSC activation. Here, we found ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, functioned to facilitate NSC activation by clearing protein aggregations through ubiquitin-proteasome approach. Upregulation of UCHL1 enhanced NSC proliferation in the spinal cord after injury. Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3+ neurotoxic reactive astrocytes negatively regulated UCHL1 and aggresome clearance through C3/C3aR signaling, resulting in reduced capacity of NSC to activate. Furthermore, blockade of reactive astrocytes or C3/C3aR pathway led to enhanced NSC activation post-SCI. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, which may provide potential molecular targets for NSC fate regulation.

neuroscience↗

bioRxiv2020

N6-methyladenine DNA demethylase ALKBH1 regulates mammalian axon regeneration

Recent studies have shown that DNA N6-methyladenine (N6-mA) modification is emerging to be a novel and important epigenetic regulator of mammalian gene transcription. Several studies demonstrated DNA N6-mA in human or rodents was regulated by methyltransferase N6AMT1 and demethylase ALKBH1. Moreover, studies in mouse brain or human glioblastoma cells showed that reduced level of N6-mA or higher level of ALKBH1 was correlated with up regulated levels of genes associated with neuronal development. We thus investigated the functional roles of ALKBH1 in sensory axon regeneration. Our results showed that ALKBH1 regulated the level of N6-mA in sensory neurons, and upon peripheral nerve injury ALKBH1 was up regulated in mouse sensory neurons. Functionally, knocking down ALKBH1 in sensory neurons resulted in reduced axon regeneration in vitro and in vivo, which could be rescued by simultaneously knocking down N6AMT1. Moreover, knocking down ALKBH1 led to decreased levels of many neurodevelopment regulatory genes, including neuritin that is well known to enhance axon growth and regeneration. Our study not only revealed a novel physiological function of DNA N6-mA, but also identified a new epigenetic mechanism regulating mammalian axon regeneration. Significance StatementThe study demonstrated that DNA N6-methyladenine (N6-mA) modification played important roles in regulation of sensory axon regeneration, likely through controlling the expression of neurodevelopmental associated genes. The results will add new evidence about the physiological function of DNA N6-mA and its regulatory demethylase ALKBH1 in neurons.

neuroscience↗

bioRxiv2019

Knocking out non-muscle myosin II in retinal ganglion cells promotes long-distance optic nerve regeneration

In addition to altered gene expression, pathological cytoskeletal dynamics in the axon are another key intrinsic barrier for axon regeneration in the central nervous system (CNS). Here we showed that knocking out myosin IIA/B in retinal ganglion cells alone either before or after optic nerve crush induced marked and sustained optic nerve regeneration. Combined Lin28 overexpression and myosin IIA/B knockout led to synergistic promoting effect and long-distance axon regeneration. Immunostaining, RNA-seq and western blot analyses revealed that myosin II deletion did not affect known axon regeneration signaling pathways or the expression of regeneration associated genes. Instead, it abolished the retraction bulb formation and significantly enhanced the axon extension efficiency. The study provided clear evidence that directly targeting neuronal cytoskeleton was sufficient to induce strong CNS axon regeneration, and combining gene expression in the soma and modified cytoskeletal dynamics in the axon was a promising approach for long-distance CNS axon regeneration.

neuroscience↗

bioRxiv2019

Neuronal histone methyltransferase EZH2 regulates neuronal morphogenesis, synaptic plasticity, and cognitive behavior of mice

Recent studies showed that in the nervous system histone methyltransferase EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) acts to regulate neural stem cell proliferation and fate specificity through silencing different gene sets. Here we explored the function of EZH2 in early post-mitotic excitatory neurons by generating a neuronal specific Ezh2 conditional knockout mouse line. The results showed that lack of neuronal EZH2 led to delayed neuronal migration, more complex dendritic arborization, and significantly increased dendritic spine density. RNA-sequencing (RNA-seq) experiments comparing control and Ezh2 knockout neurons revealed that neuronal EZH2 regulated genes related to neuronal morphogenesis. In particular, Pak3 was identified as a target gene suppressed by EZH2 and H3K27me3, and expression of dominant negative PAK3 reversed Ezh2 knockout-induced higher dendritic spine density. Lastly, lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice. Our results demonstrated that neuronal EZH2 played important roles in controlling multiple steps of neuronal morphogenesis during development, which had long-lasting effects on cognitive function in adult mice.

neuroscience↗

bioRxiv2019

The Telomerase Reverse Transcriptase (TERT) and p53 Regulate Mammalian PNS and CNS Axon Regeneration downstream of c-Myc

Although several genes have been identified to promote axon regeneration in the central nervous system, our understanding of the molecular mechanisms by which mammalian axon regeneration is regulated is still limited and fragmented. Here by using sensory axon and optic nerve regeneration as model systems, we revealed an unexpected role of telomerase reverse transcriptase (TERT) in regulation of axon regeneration. We also provided strong evidence that TERT and p53 acted downstream of c-Myc to control sensory axon regeneration. More importantly, overexpression of p53 in sensory neurons and retinal ganglion cells (RGCs) was sufficient to promote sensory axon and optic never regeneration, respectively. The study revealed a novel c-Myc-TERT-p53 signaling pathway, expanding horizons for novel approaches promoting CNS axon regeneration.

neuroscience↗

bioRxiv2018

Novel role of Lin28 signaling in regulation of mammalian PNS and CNS axon regeneration

Several signaling molecules involved in cellular reprogramming have been shown to regulate mammalian axon regeneration. We hypothesized that reprogramming factors are key regulators of axon regeneration. Here we investigated the role of Lin28, an important reprogramming factor, in the regulation of axon regeneration. We found that Lin28a and Lin28b and their regulatory partners, let-7 microRNAs (miRNAs), were both necessary and sufficient in regulating mature sensory axon regeneration in vivo. More importantly, overexpression of either Lin28a or Lin28b in mature retinal ganglion cells (RGCs) promoted robust and sustained optic nerve regeneration. Additionally, combined overexpression of Lin28a and downregulation of PTEN in RGCs acted additively to promote optic nerve regeneration by reducing the backward turning of regenerating RGC axons. Our findings not only identified a novel molecule promoting optic nerve regeneration but also suggested that reprogramming factors may play vital roles in regulating axon regeneration in mammals.

neuroscience↗