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Developmental biology - Brain function

Enhancing the Face

New research suggests gene enhancers determine facial development...

A search for cleft palate's cause reveals a new map of the facial genome. Once upon a time in Europe, pregnant women avoided rabbits to prevent their baby from being born with "harelip." But, that isn't the only misconception about how cleft lip occurs. In the May 1 issue of Cell Reports, UConn Health researchers report the popular belief that the condition is caused by a gene is also wrong. Their research could transform how we understand the formation of our face.

Clefts of the mouth and face affect up to 1 in 500 people, making it one of the most common birth defects. Sometimes the cleft is just a small indentation on a person's lip, while in other cases the cleft splits deeply into the lip, upper palate and even the nose. And most of the time, a person with a cleft has no other malformations of bones or other organs.

A few genes have been associated with facial clefts, but they account for only a very small number of cases.
"Clefts are not like other disorders caused by mutation in a gene. Generally those are syndromes affecting multiple organ systems. In most clefting cases, there is nothing else wrong."

Justin Cotney PhD, Assistant Professor, Genetics and Genome Sciences, University of Connecticut Health, USA.

Cotney studies the human genome, but not the genes that tell the body what proteins to make. Instead, he focuses on regulators, located on areas of DNA that tell genes when and where to function. These regulators are also called enhancers, and tend to be linked to specific parts of the body.

"We thought clefting cases might be frequently caused by a disruption of one of these regulatory pieces of DNA," Cotney explains. Enhancers are still not well understood. Located throughout the genome, it's often unclear which genes they control and what distances they cover on a gene.
"Even though we have the whole human genome sequence, identifying enhancers and understanding what they do is akin to trying to work from a map written in an alien language."

Justin Cotney PhD

Cotney's lab has now begun to decipher that map.

Researchers examined tissue from human facial development four to eight weeks after conception. The human face begins as a collection of folds and bulges, with each structure vital to facial function. If these structures do not move together and fuse at the proper time, clefts can occur. To identify enhancers that might be regulating facial processes, Cotney's team used molecular tags to identify which pieces of the DNA strand become active at this stage. They then compared their map of active genes to previous research to find which active DNA sequences are shared between tissues, and which are specific to face development. These face-specific enhancers, Cotney and his team believe, contribute to many cases of cleft palate.
If these enhancers are deleted, or turn on in the wrong place or the wrong time, the folds and bulges of the early face may grow in the wrong direction, or fuse together too early or not at all.

In their paper, the researchers focused on enhancers that, when deleted, are likely to cause Van Buchem Disease, a severe bone thickening disorder, or Pierre Robin Syndrome, a collection of craniofacial abnormalities including clefting. Cotney's team found thousands of previously unknown enhancers that are likely involved in building the skull as well as the face. They found that these newly recognized enhancers are commonly near parts of DNA associated with clefting or where normal differences occur in the human face.

They call their map and data collection the Human Craniofacial Epigenetic Atlas, and posted it publicly.
"We've found a large amount of regulatory architecture for craniofacial development. Now we can begin to understand which variants in our genome are likely to contribute to craniofacial abnormalities. In the future, we hope these annotations will help scientists develop targeted therapies to correct or prevent defects during pregnancy."

Justin Cotney PhD


Global profiling of histone modifications across early human craniofacial development

Chromatin state segmentation reveals enhancers with craniofacial-specific activation

Early craniofacial enhancers enriched with genetic associations for orofacial clefting

Late craniofacial enhancers enriched with genetic associations for normal facial shape

Defects in patterning during human embryonic development frequently result in craniofacial abnormalities. The gene regulatory programs that build the craniofacial complex are likely controlled by information located between genes and within intronic sequences. However, systematic identification of regulatory sequences important for forming the human face has not been performed. Here, we describe comprehensive epigenomic annotations from human embryonic craniofacial tissues and systematic comparisons with multiple tissues and cell types. We identified thousands of tissue-specific craniofacial regulatory sequences and likely causal regions for rare craniofacial abnormalities. We demonstrate significant enrichment of common variants associated with orofacial clefting in enhancers active early in embryonic development, while those associated with normal facial variation are enriched near the end of the embryonic period. These data are provided in easily accessible formats for both craniofacial researchers and clinicians to aid future experimental design and interpretation of noncoding variation in those affected by craniofacial abnormalities.

Authors: Andrea Wilderman, Jennifer VanOudenhove, Jeffrey Kron, James P. Noonan, Justin Cotney.

Funding for this work was provided by the National Institute of Dental and Craniofacial Research.

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May 3, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Development of the human face is particularly vulnerable in the first month of gestation.
Every bulge and fold must match up to its other half along a newly created central axis.
The meeting of these two sides will cover the abdomen, ribcage and skull. If there
is a mismatch when facial folds meet, a cleft forms that must be repaired after birth.
The umbilical cord extends from the abdomen, wrapped by the lower body.
Image: The Visible Embryo.

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