-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Less than 2 percent of the human genome is made up of genes that code for proteins, and the remaining 98 percent are non-coding genes that are involved in regulating gene expression
.
Scientists have found many changes in the coding regions of the genome that directly turn off genes and cause disease, and now they have found that changes in the noncoding regions of the genome also have clinical consequences
.
In a new study, researchers at the Broad Institute of MIT, Harvard University, and Massachusetts General Hospital (MGH) have found that structural variation in a noncoding region near a gene called MEF2C, a transcription factor associated with neurodevelopmental disorders NDDs, can mimic the effects of
changes in the gene itself 。 Their paper, published today in the American Journal of Human Genetics, describes for the first time the long-term effects of coding and noncoding MEF2C variants in human neuronal cell lines, noting that both indirect and direct disruption of the gene can have similar downstream effects
.
"It's a good conceptual model of how different edits, different regulatory mechanisms, and different mutation types can really affect the same gene and have a range of different consequences
for human health and disease.
" Michael Talkowski, senior author of the paper, a member of the Broad Medical and Population Genetics Project and the Stanley Center for Psychiatric Research, is also director of the Center for Genomic Medicine and faculty member
of the Department of Neurology at MGH.
It has been established that altering structural variants in MEF2C increases a person's chances of developing NDDs, including autism spectrum disorder, developmental delay, intellectual disability, epilepsy, and more
.
The gene itself is intolerant to changes — if a person inherits a altered copy of the gene, their cells won't be able to produce enough MEF2C protein (a phenomenon called haploinsufficiency), which increases the odds
of NDDs.
Scientists have been able to see the effects of haploinsufficiency in mouse models, where losing a single copy of MEF2C alters brain development and reduces electrochemical activity
in neurons.
Tarkovsky and his team, led by Harvard PhD student Kiana Mohajeri and neuroscience lecturer Rachita Yadav, wanted to demonstrate that the findings could be replicated
in human cells.
The team first evaluated the effects of MEF2C and different changes around it in neuronal cell lines from CRISPR/Cas9-edited induced pluripotent stem cells to simulate 6 different structural variants
.
They made an unexpected discovery: Cells that made specific changes at the proximal loop boundary of noncoding DNA near MEF2C, but that were not directly altered in the gene, still produced lower levels of the MEF2C protein and had difficulty transmitting electrochemical signals
.
Changes in the noncoding genome seem to fully reflect the effects
of direct changes in genes.
Talkowski said: "In cases where the genome around MEF2C is rearranged, we found the equivalent of
haploinsufficiency.
This leads to the assumption that the three-dimensional organization is destroyed, leading to what looks like a
single inadequacy.
”
The team set out to systematically explore whether certain alterations in the noncoding region around MEF2C could have similar downstream effects
as changes in genes.
They observed changes
within the topological association domain (TAD), including MEF2C.
TADs are large genomic neighborhoods containing gene and non-coding gene regulatory DNA elements that are thought to interact, making regions near MEF2C potentially a hotspot
for noncoding gene changes that scientists are looking for.
They found that neuronal cell lines carrying CRISPR-induced MEF2C changes showed lower gene expression associated with neurodevelopmental pathways and reduced
cell-to-cell electrical signaling capacity.
Studying changes in the noncoding genome is not so simple
.
The team initially thought that disrupting one edge of the MEF2C TAD — a region called the distal ring boundary — would have the same effect
as directly altering MEF2C.
But these disturbances don't seem to alter the function of
neurons.
Only when they broke the boundary at the other end of the TAD of MEF2C, the so-called proximal ring boundary, were the team able to model the effects
of the MEF2C mutation.
Neurons carrying this disturbance struggle to relay signals to neighboring neurons
.
While the findings confirm the researchers' suspicion that different mechanisms of MEF2C loss may have similar effects at the cellular level, it also raises a new set of questions
about how changes in noncoding DNA can lead to certain diseases.
The paper explores the ways in which some yet-to-be-studied genes may be disrupted, but because the relationship between gene regulation and expression is multilayered, scientists need to dig deeper to better understand the mechanisms
underlying changes in noncoding genomes and cellular and clinical outcomes.
"The regulation that controls these complex neurodevelopmental genes is so complex that we've experimentally analyzed some of them, but we're not even close to capturing the full picture
," Talkowski said.
