CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
Developmental biology - Brain function|
Enhancing the Face
"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."
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."
• 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.
Return to top of page
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.