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

The epigenetic regulator, MLL4 ( KMT2D ), has been described as an essential gene in both humans and mice[1][1],[2][2]. In addition, it is one of the most commonly mutated genes in all of cancer biology[3][3]–[7][4]. Here, we identify a critical role for Mll4 in the promotion of epidermal differentiation and ferroptosis, a key mechanism of tumor suppression[8][5],[9][6]. 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][7]. 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. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-7 [5]: #ref-8 [6]: #ref-9 [7]: #ref-10