Methyl-CpG Binding Protein 2 (Mecp2) Regulates Quiescence Exit and Tissue Regeneration

Conceitos essenciais

Mecp2 is a critical negative regulator of quiescence exit, which fine-tunes the balance between metabolism and proliferation during tissue regeneration.

Resumo

The study investigates the role of methyl-CpG binding protein 2 (Mecp2) in regulating quiescence exit and tissue regeneration. Key findings:

Mecp2 expression is cell cycle-dependent, with a sharp decline during the G0/G1 transition in both in vivo liver regeneration and in vitro cellular models of quiescence exit.

Hepatocyte-specific Mecp2 depletion accelerates quiescence exit and liver regeneration, while Mecp2 overexpression delays quiescence exit.

The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, facilitating quiescence exit.

Genome-wide analysis reveals that Mecp2 governs quiescence exit by transcriptionally activating metabolic genes, including several nuclear receptors (NRs), while repressing proliferation-associated genes.

Disruption of two Mecp2-activated NRs, Rara and Nr1h3, mimics the Mecp2 depletion phenotype and further enhances quiescence exit in Mecp2-deficient livers.

In summary, the study uncovers a critical negative regulatory role for Mecp2 in fine-tuning the balance between metabolism and proliferation during quiescence exit and tissue regeneration.

Estatísticas

Mecp2 mRNA levels were significantly decreased at 6, 12, and 24 hours after partial hepatectomy (PHx) in mouse livers.
Mecp2 protein levels were dramatically reduced as early as 6 hours after PHx, further decreased at 12 and 24 hours, but were restored at 48 and 120 hours.
Hepatocyte-specific Mecp2 depletion significantly enhanced liver regeneration at 6, 12, 24, and 48 hours after PHx.
Mecp2 overexpression in hepatocytes significantly delayed cell cycle reentry and liver regeneration within 24 hours after PHx.
Nedd4 knockdown attenuated the reduction of Mecp2 and delayed quiescence exit in 3T3 cells.
Rara or Nr1h3 knockdown accelerated quiescence exit in 3T3 cells, mimicking the effect of Mecp2 depletion.
Rara or Nr1h3 knockdown further enhanced quiescence exit in Mecp2-deficient livers.

Citações

"Mecp2 is a critical negative regulator of quiescence exit, which fine-tunes the balance between metabolism and proliferation during tissue regeneration."
"The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, facilitating quiescence exit."
"Mecp2 governs quiescence exit by transcriptionally activating metabolic genes, including several nuclear receptors (NRs), while repressing proliferation-associated genes."

Principais Insights Extraídos De

Mecp2 Fine-tunes Quiescence Exit by Targeting Nuclear Receptors

by Yang,J., Zou... às www.biorxiv.org 07-24-2023

https://www.biorxiv.org/content/10.1101/2023.07.24.550263v2

Perguntas Mais Profundas

How do the transcriptional regulatory mechanisms of Mecp2 differ between quiescent and proliferating cells?

In quiescent cells, Mecp2 is maintained at relatively high levels and serves as both a transcriptional activator and repressor. It binds to and activates metabolic genes, such as several nuclear receptors (NRs), while repressing proliferation-associated genes. This balance between activation and repression of different gene sets helps maintain the quiescent state. However, upon receiving extrinsic signals for cell cycle reentry, the protein levels of Mecp2 are acutely decreased by both transcriptional repression and Nedd4-mediated ubiquitination. This reduction of Mecp2 releases the transcriptional repression of proliferation-associated genes while compromising the activation of metabolic genes, allowing the cells to transition from quiescence to active proliferation.

What other factors or signaling pathways interact with Mecp2 to modulate the balance between metabolism and proliferation during quiescence exit?

In addition to Nedd4-mediated ubiquitination, other factors and signaling pathways may interact with Mecp2 to modulate the balance between metabolism and proliferation during quiescence exit. One such factor is the nuclear receptors (NRs) that are transcriptionally regulated by Mecp2. These NRs, such as Rara and Nr1h3, play crucial roles in regulating cellular metabolism and proliferation. By repressing the expression of these NRs, Mecp2 can shift the transcriptional program towards promoting proliferation over metabolism during quiescence exit. Additionally, other post-translational modifications of Mecp2, such as phosphorylation and acetylation, may also influence its regulatory functions in balancing metabolism and proliferation.

Could the Mecp2-NR axis be targeted to enhance tissue regeneration or suppress uncontrolled cell proliferation in disease conditions?

The Mecp2-NR axis, particularly the regulation of NRs by Mecp2 during quiescence exit, presents a potential therapeutic target for enhancing tissue regeneration or suppressing uncontrolled cell proliferation in disease conditions. By modulating the expression or activity of specific NRs, such as Rara and Nr1h3, it may be possible to fine-tune the balance between metabolism and proliferation in cells undergoing quiescence exit. Targeting this axis could help promote controlled cell proliferation during tissue regeneration or inhibit excessive proliferation in conditions like cancer. Further research into the specific mechanisms and downstream effects of targeting the Mecp2-NR axis is needed to explore its therapeutic potential in various disease contexts.