DNA Methylation Plays Key Role in Stem Cell Differentiation

Source: Northwestern University

Summary: According to a new study, researchers have discovered how the process of DNA methylation regulates the development of spinal cord motor neurons.

DNA methylation, an epigenetic mechanism that determines whether or not a gene is expressed, guides stem cells as they transform from blank slates into specialized cells. Motor neurons are highly specialized neuronal cells that connect the central nervous system to muscle and degenerate in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. Looking at DNA methylation patterns in ALS patients, they are all over the place. Is it a driver of disease, or is it just a byproduct? This study provides us with a platform to address these intriguing questions. Researchers from the Northwestern University have discovered how the process of DNA methylation regulates the development of spinal cord motor neurons. The study findings were published in the journal Cell Stem Cell.

Neural progenitors are cells that are capable of dividing a limited number of times

Neural progenitors cells differentiated from human embryonic stem cells. Credit: Northwestern University

The investigators used a variety of cutting-edge technologies including single cell RNA-Sequencing and a methylation-focused adaption of CRISPR-Cas9 gene editing, known as epigenetic editing to create a series of stem cells that each lacked different enzymes that trigger DNA methylation. After analyzing the stem cells along with the differentiating neural progenitors and the motor neuron populations, concluded that the enzyme DNMT3A triggered DNA methylation, which in turn repressed or counterintuitively activated the key transcription factors that controlled differentiation of stem cells into spinal cord motor neurons. In addition, they found irregular DNA methylation patterns could have downstream consequences related to the function of these neurons. Further investigation could shed light on spinal cord diseases.

Asst. Prof. Evangelos Kiskinis said, “It seems if you don’t set your DNA methylation patterns correctly, there’s a cascade of irregular gene expression that results in defective cells”, “This is intriguing, because people usually think about methylation in the context of cell differentiation, the role in developed neurons is largely overlooked.”

More Information: Michael J. Ziller et al, “Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology”, Cell Stem Cell (2018). DOI: 10.1016/j.stem.2018.02.012 

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