Long-range enhancers regulating Myc expression are required for normal facial morphogenesis.

Area of Science:

• Genetics
• Developmental Biology
• Human Congenital Malformations

Background:

• Cleft lip with or without cleft palate (CL/P) is a common congenital malformation, affecting 1 in 500-1,000 births.
• A specific 640-kb noncoding region at 8q24 is linked to non-syndromic CL/P risk, but the underlying genes and pathways are unknown.

Purpose of the Study:

• To investigate the function of the 8q24 noncoding interval associated with CL/P risk.
• To identify genes and molecular pathways involved in craniofacial development regulated by this region.

Main Methods:

• Engineered rearrangements in the syntenic mouse region corresponding to human 8q24.
• Analyzed effects on facial morphology and Myc expression in mice.
• Investigated downstream gene misexpression and cellular metabolic impact.

Main Results:

• The 8q24 interval contains remote cis-acting enhancers controlling Myc expression during facial development.
• Deletion of this interval in mice caused mild facial alterations and sporadic CL/P.
• Identified misexpression of downstream genes affecting craniofacial development and cell metabolism.

Conclusions:

• The 8q24 noncoding region harbors enhancers critical for facial development.
• A dual molecular etiology, impacting both craniofacial development and cellular metabolism, likely explains the association of 8q24 variants with human facial dysmorphies.