Abstract
The basal layer of human epidermis is composed of progenitor cells that both self-renew and differentiate to form stratified epidermal tissue; this process requires strict, dynamic regulation of gene expression. The Super Elongation Complex (SEC) regulates gene expression at the level of transcription elongation by releasing RNA Polymerase II from its paused state. Dysregulation of the SEC has been identified in leukemia and fragile X syndrome, but how the SEC functions in somatic tissue homeostasis has not been characterized. To better understand the role of the SEC, we performed a knockdown and an evolutionary analysis of the SEC’s mutually exclusive scaffolding subunits, AFF1 and AFF4. Our data revealed a difference in function between AFF1 and AFF4. Knockdown of AFF1, but not AFF4, resulted in increased expression of epidermal differentiation genes, suggesting that AFF1-SEC may function as a transcription inhibitor to promote progenitor maintenance. The evolutionary analysis revealed that Homo sapiens AFF1, but not AFF4, has a region of homology to both the Atrophin and Herpes ICP4 protein domains, both of which possess inhibitory activity. Given that Drosophila melanogaster has only one AFF homologue, this analysis suggests that AFF proteins evolved novel functions to promote more complex patterns of gene expression in higher-order species. The observed differences between AFF1 and AFF4 suggest a mechanism through which the SEC selectively utilizes AFF1 to suppress expression of differentiation genes in order to maintain cells in the progenitor state.