Summary: Experts have uncovered how reduction of the MeCP2 protein triggers beginning chemical changes leading to Rett symptoms, a serious neurological disorder. By studying child mice, they established that MeCP2 damage disrupts gene expression well before observable neural deficits occur.
The results demonstrate that MeCP2 function causes both increased and decreased expression of genes essential for neuronal function. This study provides possible targets for first Rett syndrome intervention in a crucial window where chemical events take place.
Essential Information
- First Gene Changes: Lost of MeCP2 leads to fast gene expression regulation, affecting hundreds of genes.
- Cerebral Effect: Dysregulated chromosomes are linked to cerebral work, causing downstream circuit-level imbalances.
- Medical Window: The investigation reveals a time frame between chemical changes and cerebral symptoms, enabling early treatment options.
Origin: Baylor College of Medicine
Researchers at , Baylor College of Medicine,  , Jan and Dan Duncan Neurological Research Institute , ( Duncan NRI ) at Texas Children’s Hospital and collaborating institutions have gained new insights into the molecular changes leading to Rett syndrome, a severe neurological disorder caused by mutations in the , MeCP2 , gene encoding methyl-CpG binding protein 2 ( MeCP2 ).
The group reports in the journal , Neuron , that lost of , MeCP2 , in adult causes quick liberal dysregulation of hundreds of genes– some are activated while others are suppressed – and these changes occur nicely before any measurable deficiencies in neurological function.
The MeCP2 proteins is most extremely expressed in cells – brain cell where, like an ensemble wire, MeCP2 directs the appearance of hundreds of genes.
When a nonfunctional MeCP2 protein is produced by a mutation, the conductor no longer serves as the coordinating authority for the peaceful expression of the genes required for normal brain function. Rett syndrome is a result of the gene expression conflict.
” In the current review, our objective was to better comprehend the chemical changes that occur upon reduction of MeCP2 function. Past studies have attempted to accomplish this by studying the situation in animals that exhibit extreme disorder symptoms.
” But, it has been difficult to separate the chemical changes caused by loss of , MeCP2 , from those occurring during growth or secondary to ill neurons,” said initial author , Dr. Sameer S. Bajikar, who was working in the , lab , of , Dr. Huda Zoghbi , during most of this project.
At the University of Virginia, Bajikar is currently an assistant professor.
Many genes are expressed and suppressed while the development of an organism occurs, and many “harmonies” are played simultaneously to create a complex composition. It can be challenging to distinguish the harmonies emerging from the lack of , MeCP2 , from the others.
The researchers looked for a way to simplify the complex harmonies so they would be able to identify those coming from , MeCP2 , dysregulation. Knowing that , MeCP2 , function is required throughout life, that the , MeCP2 , director is active during the entire life of an organism, inspired the researchers to focus on adult life, a time past development, when there are no more developmental compositions playing.
” We conditionally deleted , Mecp2 , in adult mice, which reproduces all the characteristic deficits and premature death observed in male animals in which the , Mecp2 , is deleted from conception. Then, we systematically assessed gene expression, as well as events involved in gene expression regulation, at multiple times after adult loss of , Mecp2,” Bajikar said.
” We found that adult deletion of , Mecp2 , changes the expression of many genes very early after , Mecp2 , loss, some genes ‘ expression was increased while others reduced. These gene expression changes became more robust over time and mirrored those of the , Mecp2 , germline knockout mice.
” These data revealed a molecular cascade that drives disease independent of any developmental contributions – we were able to identify the’ harmonies ‘ coming from , MeCP2 , dysregulation”.
Additionally, the researchers discovered that both the genes that are persistently upregulated and downregulated are highly methyl chemically tagged. Their expression is regulated by cytosine methylation within and near genes.
Many of the genes dysregulated due to , MeCP2 , loss are directly related to neuronal function, and some of these genes have been directly shown to modulate , MeCP2-driven disease.
A key finding from this study is that neuronal circuit-level deficits occurred after gene expression dysregulation, suggesting , Mecp2 , deletion leads to bidirectional dysregulation of gene expression first and that in turn contributes to reduced neuronal function.
Our research also provides information on genes essential for proper neuronal function that are dysregulated downstream of MeCP2 but upstream of circuit-level deficits. These genes warrant further study”, said Zoghbi, Distinguished Service Professor at , Baylor, director of the Duncan NRI and a , Howard Hughes Medical Institute , investigator.
” Lastly, our data demonstrate that there is a window of time when molecular events downstream of , MeCP2 , are occurring, but before overt physiological consequences are measurable”, Zoghbi said.
” The analysis of specific changes during this time frame will be crucial for fully characterizing the molecular event cycle that causes Rett syndrome.”
Jian Zhou, RyanO’Hara, Harini P. Tirumala, Mark A. Durham, Alexander J. Trostle, Michelle Dias, Yingyao Shao, Hu Chen, Wei Wang, Hari K. Yalamanchili, Ying-Wooi Wan, Laura A. Banaszynski and Zhandong Liu also contributed to this work.
The authors are affiliated with one of more of the following institutions: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and UT Southwestern Medical Center, Dallas.
Funding: This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Development ( F32HD100048, R01HD109239, U54HD083092 ), National Institute of Neurological Disorders and Stroke ( R01NS057819, K99/R00NS129963 ), National Institute of General Medical Sciences ( R35GM124958 ), The Welch Foundation (I-2025 ), American Cancer Society ( 134230-RSG-20-043-01-DMC), Duncan NRI Zoghbi Scholar Award through Texas Children’s Hospital, the International Rett Syndrome Foundation ( 4013 ) and the Howard Hughes Medical Institute.
About this news about genetics and Rett syndrome research
Author: Graciela Gutierrez
Source: Baylor College of Medicine
Contact: Graciela Gutierrez – Baylor College of Medicine
Image: The image is credited to Neuroscience News
Original Research: Open access.
Sameer S. Bajikar and colleagues ‘” Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that inform the pathogenic cascade”. Neuron
Abstract
In adult mice, acute MeCP2 loss reveals chromatin and transcriptional changes that predate neurological dysfunction and inform the pathogenic cascade.
Mutations in the X-linked methyl-CpG-binding protein 2 ( MECP2 ) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions.
To understand what drives such dysregulation, we deleted , Mecp2 , in adult mice, circumventing developmental contributions and secondary pathogenesis.
We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We discover that the loss of MeCP2 results in bidirectional and immediate progressive dysregulation of the transcriptome.
We profiled genome-wide histone modifications to understand what causes gene downregulation. We found that one of the earliest molecular changes to occur well before any observable deficiencies in electrophysiology and neurological function.
These findings reveal a molecular cascade that causes disease regardless of any changes in development or secondary pathogenesis.
