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Project

Assessment of the contribution of developmental enhancers in craniofacial disorders

Craniofacial malformations are among the most common congenital anomalies in humans (1/1600 newborns). They have significant psychosocial consequences and direct implications in basic functions such as speech or feeding. While it is evident that human face shape is highly heritable, the genetic bases of craniofacial development, and consequently the genetic causes of many craniofacial disorders, remain largely unknown. In recent years, developmental enhancers have been shown to play an active role in craniofacial development by controlling the spatial and temporal regulation of several craniofacial gene regulatory networks. More specifically, we and others, have identified craniofacial-specific enhancers, characterized their activity, and shown that their sequence variation (deletion or single base-pair mutations) could alter normal gene expression programs and induce normal or pathological skull morphological changes. A major challenge in understanding the role of enhancers in developmental processes is related to their ability to regulate genes over large distances and in disentangling the importance and hierarchy of regulatory signals at (craniofacial) gene regulatory landscapes. To tackle those issues and gain insights into the molecular functions of enhancers, we have recently obtained gene(s)-enhancer(s) chromatin interaction maps of the early embryonic mouse facial prominences. These reveal a total of 327’459 unique interactions, out of which 77% are of the gene-intergenic type. Enrichment analyses with matched epigenomic data also show that these interactions are significantly enriched for craniofacial regulatory sequences and thus can be used to dissect the regulatory landscape of known craniofacial genes or craniofacial-associated GWAS loci. Finally, our data also points toward novel putative craniofacial genes and regulatory sequences. In this translational research project we aim to link basic research on craniofacial enhancers with clinical / diagnostic research in craniofacial disorders.

Date:1 Jul 2022 →  Today
Keywords:craniofacial, enhancer activity, gene regulation
Disciplines:Genome structure and regulation
Project type:PhD project