Rajalaxmi Natarajan, Ph.D.
September 19, 2017
Researchers in the laboratory of
Dr. Benjamin Deneen, investigator at
the Jan and Dan Duncan Neurological Research Institute at
Texas Children's Hospital and associate professor at
Baylor College of Medicine, have identified mechanisms in which
NFIA, a glial gene, is regulated during normal brain development
and in brain tumors. The study published in Nature Neuroscience
journal opens new avenues to develop therapies for glioma.
The Deneen lab had previously implicated NFIA in the formation
of gliomas which are among the deadliest forms of cancer.
Validating the biological role of enhancers is usually
challenging and most researchers use bioinformatics methods to
predict putative enhancer regions.
In this study, the researchers used a powerful in
vivo system to screen known neuronal enhancers to find
which of those could developmentally regulate NF1A expression.
Using developing embryonic chick spinal cords, they were able to
biologically validate the function of three distinct enhancers for
the NFIA gene.
In this study, researchers explored how three layers of
regulatory controls, the long-range DNA elements known as
enhancers, regulatory proteins known as transcription factors and
novel three-dimensional DNA loops, act together to differentially
express NFIA gene in glial and neuronal lineages.
During different stages of development, genes are turned on or
off in specific tissues and cellular lineages. Various regulatory
mechanisms act in coordination to regulate this complex web of gene
expression. In the spinal cord, the NFIA gene is specifically
expressed in glial cells and its expression is switched off in
neurons. Glia comprises 70 percent of the cells in the nervous
system and supports the function of neurons.
While scientists have a basic understanding of how these
regulatory factors function individually, this study provides the
first glimpse into how these regulatory processes cooperate and act
together with one another to control gene expression.
Further experiments in mice models showed these three long-range
enhancers cooperatively regulate NFIA expression in glia and
neurons by binding to distinct lineage-specific transcription
factor proteins. Interestingly, researchers found that the region
of the NFIA gene that contains these enhancers assumes two distinct
three-dimensional conformations in glia and neurons. Furthermore,
they demonstrated that these loops preform and provide a permissive
configuration for the correct lineage-specific transcription
factors to bind to their enhancers.
This pioneering study has identified novel regulatory mechanisms
and intermediates, which would be ideal targets to develop specific
therapies for gliomas. The researchers were excited to observe that
disrupting these 3-D loops decreased NFIA expression reduced glial
proliferation and reduced the size of the tumors.