Tissue-specific nuclear membrane proteins direct 3D genome organization changes important for fat and muscle differentiation and disease Event

Event details

Different tissues have specific 3D genome organization patterns and it is clear that disruption of genome organization can lead to changes in gene regulation and even to human disease. In fact it has been suggested that a majority of the disease alleles remaining to be identified likely occur in non-coding regions where they could disrupt spatial contributions to genome regulation. Despite this there is very little understanding of how tissue-specific 3D genome organization patterns are established. We have found several tissue-specific nuclear envelope transmembrane proteins (NETs) from muscle and fat that are each important for establishing genome organization patterns in their respective tissues. Each affects the positioning and expression of distinct sets of important genes for tissue functioning and/or differentiation. Interestingly, many genes are recruited by these NETs to the nuclear envelope to enhance their repression and fat-specific NETs recruit several myogenic genes to be repressed while muscle-specific NETs recruit several fat metabolism genes to be repressed. Thus, the cell is apparently able to better achieve its fat or muscle identify by enhancing repression of the alternate differentiation pathway. The nuclear envelope has been linked to a wide range of human diseases that tend to have tissue-specific pathologies, even though many of the linked proteins are widely expressed. We postulate that these tissue-specific NETs mediate these pathologies through disruption of genome organization. Compellingly, we found mutations in muscle gene repositioning NETs PPAPDC3, Tmem38a, Tmem201 and Tmem214 in Emery-Dreifuss muscular dystrophy patients and a mouse knockout of a fat gene repositioning NET, Tmem120A, yields a lipodystrophic phenotype, consistent with this hypothesis.