Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli

Abstract

Summary Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-null microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1creER increased the lifespan of otherwise Mecp2-null mice. These data suggest Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages may contribute to the systemic pathologies observed in Rett syndrome.

MECP2 disorders: from the clinic to mice and back

“…Although careful studthat MeCP2 is required for general neuronal health is underscored by the dysfunction associated with the many different neuronspecific Mecp2 KOs (43,61,(63)(64)(65). In contrast, removal of MeCP2 from astrocytes or microglia results in mild behavioral phenotypes without affecting lifespan (66,67). Thus, the function of MeCP2 in the glial cell types assayed does not appear to drive pathogenesis, though Mecp2 expression in astrocytes improves the breathing symptoms of mice lacking MeCP2 in all other cell types (66).…”

Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice

“…It was previously shown that MeCP2-overexpressing mice have increased corticosterone release after stress (25), and multiple groups have directly linked MeCP2 to glucocorticoid response (13,23,24), which may explain the increased corticosterone we observed during influenza infection in MeCP2 Tg3 mice. In addition, glucocorticoids can suppress the function of and cause apoptosis in lymphocytes (26), potentially helping to explain the deficiency and impairment of lymphocytes seen late during infection.…”

“…Previous reports have implicated MeCP2 in the control of glucocorticoid response (13,23,24). In addition, MeCP2-overexpressing mice have been shown to have an enhanced response to stress (25).…”

“…It was previously shown that MeCP2 plays an important role in immune cells, including T cells (7)(8)(9)(10) and myeloid cells (11)(12)(13)(14)(15)(16), and thus it was hypothesized that chronic infections seen in MeCP2 duplication syndrome may be explained by the direct role of MeCP2 in immune cells. In 2012, Yang et al demonstrated that CD4 + T cells overexpressing MeCP2 in both mice and humans were deficient in IFN-γ production after skewing to Th1 in vitro, and that MeCP2 Tg3 mice (17), which have a human MeCP2 gene inserted into their genome and overexpress MeCP2 at levels 3-Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively.…”

Tagging Methyl-CpG-Binding Domain Proteins Reveals Different Spatiotemporal Expression and Supports Distinct Functions

“…For example, MBD2 has a role in T-cell development that is partially dependent on the methylation status of critical genes such as Foxp3 [50,66], but also has a role in the innate immune system to indirectly affect T-cell activation and differentiation [49]. Interestingly, both MeCP2 and MBD1 have also been implicated in innate and adaptive immunity [67][68][69] indicating that MBD family proteins may have a wider role in these systems. In the intestine, loss of MBD2 is linked to altered gene expression [61].…”