Summary: A new study reveals the critical function of the protein Kdm1a in maintaining neuronal identity and preventing the premature aging of neurons. Through experiments in mice and corroborated by human data, researchers found that Kdm1a suppresses inappropriate gene expression, preserving the epigenetic barriers that distinguish active and inactive chromatin regions.
The loss of Kdm1a results in the disruption of these barriers and the activation of genes that should remain silent, mirroring the effects of natural aging and contributing to neurological disorders. This research underscores the importance of epigenetic regulation in neuronal health and offers insights into the mechanisms of aging and disease.
Key Facts:
- The protein Kdm1a is essential for preserving the identity of neurons by repressing genes that should not be expressed, highlighting its role in epigenetic regulation.
- Loss of Kdm1a mirrors aging processes by activating inappropriate gene expression, suggesting its involvement in neuronal aging and potential intellectual disabilities.
- The study, supported by significant funding sources, combines mouse model research with human data analysis, demonstrating the universal relevance of Kdm1a in maintaining neuronal integrity across species.
Source: UMH
Epigenetic processes allow different cell types to emerge from a single genome. Throughout development, cells differentiate and acquire distinct characteristics by expressing the same genome in different ways. However, a less-known aspect of this process is how cells maintain their unique identities over time.
A study led by the Transcriptional and Epigenetic Mechanisms of Neuronal Plasticity laboratory, headed by Angel Barco at the Institute for Neurosciences, a joint center of the Spanish National Research Council (CSIC) and the Miguel Hernández University (UMH) of Elche, has determined that the protein Kdm1a plays a crucial role in preserving the identity of neurons.
Neurons are cells that have a very particular nuclear structure because once they are formed during development they never divide again, which is why neurons need to precisely maintain their identity throughout their lifespan.
“Identity is given by what is done and what is not done; at an epigenetic level this translates into the genes that are expressed, but also in those that are not expressed” explains Angel Barco.
The results of this study, published in the journal Nature Communications, demonstrate that deleting Kdm1a in forebrain neurons in adult mice triggers the expression of genes that normally should not be expressed in neurons, which compromises neuronal identity.
The researchers verified that in normal elderly mice, there is an incipient activation of the same genes derepressed in mice that have lost Kdm1a, indicating that natural aging reproduces the same defects as the lack of Kdm1a, although on a smaller scale.
They found that eliminating this protein accelerates neuronal aging at an epigenetic level and alters gene transcription.
The experts correlated these findings with human data by collaborating with researcher José Vicente Sánchez Mut, who leads the Functional Epi-Genomics of Aging and Alzheimer’s Disease laboratory at the IN. They used a database of people between 50 and 80 years old and found that there is also a significant increase in the expression of some of these typically silent genes as people age.
Furthermore, this work shows that the repressive function of Kdm1a maintains the separation between genes that should be expressed and those that should be silent through the modulation of chromatin structure.
The separation into “compartments” allows the maintenance of order throughout the lifespan of the neuron, which is essential to preserve its identity: “We know that disorder can have detrimental effects, both in aging and in intellectual disability because it blurs the barrier between what should be expressed and what should not,” says Beatriz del Blanco, first author of the article.
To understand the role of Kmd1a in compartmentalization, the researchers conducted an experiment, in collaboration with Yijun Ruan, former director of the Jackson Laboratory for Genomic Medicine, in which they used a technique that shows how DNA folds inside the cell nucleus, and how it is organized in three dimensions.
These data were contrasted with images obtained using super-resolution microscopy. Both approaches indicated that some repressed genes began to be expressed because the barriers that delimit active and inactive areas of the chromatin are weakened after Kdm1a loss.
The laboratory directed by Barco at the IN investigates rare neurological disorders linked to mutations in genes encoding epigenetic regulators. Mutations in the Kmd1a protein during development have been associated with an extremely rare intellectual disability disorder known as Cleft Palate, Psychomotor Delay, Distinctive Facial Features, and Intellectual Disability (CPRF Syndrome). Angel Barco emphasizes the importance of studying rare diseases to expand the limits of knowledge in this field.
Funding: This work has been possible thanks to funding from the Spanish Research Agency-Ministry of Science, Innovation, and Universities and the Fundació la Marató de TV3, among other sources.
About this neuroscience research news
Author: Angeles Gallar
Source: UMH
Contact: Angeles Gallar – UMH
Image: The image is credited to Barco, A. Instituto de Neurociencias UMH-CSIC
Original Research: Open access.
“Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons” by Barco, A et al. Nature Communications
Abstract
Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons
Kdm1a is a histone demethylase linked to intellectual disability with essential roles during gastrulation and the terminal differentiation of specialized cell types, including neurons, that remains highly expressed in the adult brain.
To explore Kdm1a’s function in adult neurons, we develop inducible and forebrain-restricted Kdm1a knockouts.
By applying multi-omic transcriptome, epigenome and chromatin conformation data, combined with super-resolution microscopy, we find that Kdm1a elimination causes the neuronal activation of nonneuronal genes that are silenced by the polycomb repressor complex and interspersed with active genes.
Functional assays demonstrate that the N-terminus of Kdm1a contains an intrinsically disordered region that is essential to segregate Kdm1a-repressed genes from the neighboring active chromatin environment.
Finally, we show that the segregation of Kdm1a-target genes is weakened in neurons during natural aging, underscoring the role of Kdm1a safeguarding neuronal genome organization and gene silencing throughout life.
