MLL4 is a critical mediator of differentiation and ferroptosis in the epidermis

Abstract

The epigenetic regulator, MLL4 (KMT2D), has been described as an essential gene in both humans and mice1,2. In addition, it is one of the most commonly mutated genes in all of cancer biology3-7. Here, we identify a critical role for Mll4 in the promotion of epidermal differentiation and ferroptosis, a key mechanism of tumor suppression8,9. Mice lacking epidermal Mll4, but not the related enzyme Mll3 (Kmt2c), display features of impaired differentiation and human pre-cancerous neoplasms, including epidermal hyperplasia, atypical keratinocytes, and a loss of polarization, all of which progress with age. Mll4 deficiency profoundly alters epidermal gene expression, and uniquely rewires the expression of key genes and markers of ferroptosis (Alox12, Alox12b, Aloxe3)10. Beyond identifying a novel role for Mll4-mediated tumor suppression in the skin, our data reveal a potentially much more broad and general role for ferroptosis in the process of epidermal differentiation and skin homeostasis.