Abstract
Chromatin modifiers play a crucial role in maintaining cell identity through modulation of gene expression patterns. Their deregulation can have profound effects on cell fate and functions. Among epigenetic regulators, the MECP2 protein is particularly attractive. Mutations in the Mecp2 gene are responsible for more than 90% of cases of Rett syndrome (RTT), a progressive neurodevelopmental disorder. As a chromatin modulator, MECP2 can have a key role in the government of stem cell biology. Previously, we showed that deregulated MECP2 expression triggers senescence in mesenchymal stromal cells (MSCs) from (RTT) patients. Over the last few decades, it has emerged that senescent cells show alterations in the metabolic state. Metabolic changes related to stem cell senescence are particularly detrimental, since they contribute to the exhaustion of stem cell compartments, which in turn determine the falling in tissue renewal and functionality. Herein, we dissect the role of impaired MECP2 function in triggering senescence along with other senescence-related aspects, such as metabolism, in MSCs from a mouse model of RTT. We found that MECP2 deficiencies lead to senescence and impaired mitochondrial energy production. Our results support the idea that an alteration in mitochondria metabolic functions could play an important role in the pathogenesis of RTT.
Highlights
In a previous in vitro study, we demonstrated that even the partial silencing of the Mecp2 gene may impair stem cell biology [3]
As progenitors of osteocytes, studying mesenchymal stromal cells (MSCs) biology could be of interest, since it has been reported that Rett syndrome (RTT) patients develop several skeletal abnormalities, such as low bone density, high frequency of fractures, and scoliosis [24]
Our findings shed light on the dysfunctions related to impaired methyl-CpG binding protein 2 (MECP2) activity that contribute to RTT symptoms
Summary
Rett syndrome (RTT; OMIM #312750) is a complex and devastating neurodevelopmental disease caused in more than 90% of RTT cases by loss-of-function mutations in the X-linked Mecp gene encoding methyl-CpG binding protein 2 (MECP2) [1]. The MECP2 protein was initially identified as a transcriptional repressor given its capacity to bind methylated DNA and mediate gene silencing by triggering modification of chromatin architecture [2,3]. Later, it was described as a multifunctional modulator of gene expression with activating or repressing functions depending on the molecular context [4]. We showed that mesenchymal stromal cells (MSCs) obtained from the bone marrow of RTT patients are prone to senescence [8] These results were validated in an in vitro model of MECP2 partial silencing [3]. We demonstrated that mouse neural stem cells with impaired MECP2 function are affected by premature senescence [7,9]
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