MITF-M-dependent gene expression

MITF is a basic helix loop helix leucine zipper (BHLH-ZIP)-containing protein and binds DNA as a dimer - either as a homodimer or as a heterodimer with the related transcription factors TFEB, TFE3, and TFEC. TFEB and TFE3 are both widely expressed, but TFEC displays more restricted expression. In this pathway, for simplicity, MITF is shown binding DNA exclusively as a homodimer (reviewed in Goding and Arnheiter, 2019).

MITF and related BHLH protein family members bind to an E-box-like element with sequence CANNTG. Specificity of binding is determined both by the flanking nucleotides and by the identity of the two internal nucleotides of the E-box element. MITF binds preferentially to sequences CATGTG or CACGTG, and binds with less affinity to the CAGCTG sequences preferred by other BHLH proteins such as AP4. High-affinity MITF-binding sites also show an enrichment for flanking 5'T and 3'A, further distinguishing these sites from those preferentially bound by transcription factors such as MYC and MAX. Variants of high-affinity MITF binding sites present in the promoters of pigmentation genes are called M-boxes, to distinguish them from related E-box sequences (reviewed in Goding and Arnheiter, 2019). Direct targets of MITF-M have been identified by ChIP-seq and CUT-and-RUN analysis in a number of primary and melanoma cell lines. In one of these studies, high-throughput ChIP-seq in the human melanoma cell line 501Mel identified MITF-binding at 5578 potential target genes, with 2771 showing promoter-proximal binding; only a subset of these genes were shown to be directly regulated by MITF, however (465; 240 down-regulated upon MITF knockdown, and 225 upregulated upon MITF overexpression) (Strub et al, 2001; reviewed in Goding and Arnheiter, 2019). MITF-bound genes included those involved in melanocyte biogenesis as well as DNA replication, repair and mitosis. Other studies have identified roles for MITF-M as a direct repressor of a number of genes implicated in estracellular matrix organization, cell adhesion, invasion and epithelial-to-mesenchymal transition (Laurette et al, 2015; Dilshat et al, 2021; reviewed Rambow et al, 2019).