While these mechanisms have been widely studied in cancer and general development, we focused on the evolutionary conserved counteracting activities of H3K36 (SETD2, SETD5, NSD1, NSD2, and ASH1L), and H3K4 (MLL1/KMT2A, MLL2/KMT2B, MLL3/KMT2C, MLL4/KMT2D, SETD1A, and SETD1B) modifiers vs. PcG (PRC2), because their antagonizing activities are understudied in the regulation of brain architecture, wiring and brain size control (Figures 1, 2 and Tables 1–4). This evidence concerns the gene KMT2D and cancer.