MLL4 is required for the first embryonic collective cell migration whereas MLL3 is not required until birth

Abstract Methylation of histone 3 lysine 4 (H3K4) is a major epigenetic system associated with gene expression. In mammals there are six H3K4 methyltransferases related to yeast Set1 and fly Trithorax, including two orthologs of fly Trithorax-related: MLL3 and MLL4. Exome sequencing has documented high frequencies of Mll3 and Mll4 mutations in many types of human cancer. Despite this emerging importance, the requirements of these sister genes in mammalian development have only been incompletely reported. Here we examined the null phenotypes to establish that MLL3 is first required for lung maturation whereas MLL4 is first required for migration of the anterior visceral endoderm (AVE) that initiates gastrulation and is the first collective cell migration in development. This migration is preceded by a columnar to squamous transition in visceral endoderm cells that depends on MLL4. Furthermore, Mll4 mutants display incompletely penetrant, sex distorted, embryonic haploinsufficiency and adult heterozygous mutants show aspects of Kabuki syndrome, indicating that MLL4 action, unlike MLL3, is dosage dependent. The highly specific and discordant functions of these sister genes argues against their action as general enhancer factors. Summary statement The H3K4 methyltransferases MLL3 and MLL4 have strikingly different null phenotypes during mouse development; MLL3 is required for lung maturation whereas MLL4 is required for anterior visceral endoderm migration.