Beyond MITF: Multiple transcription factors directly regulate the cellular phenotype in melanocytes and melanoma

Abstract

Summary MITF governs multiple steps in the development of melanocytes, including specification from neural crest, growth, survival, and terminal differentiation. In addition, the level of MITF activity determines the phenotype adopted by melanoma cells, whether invasive, proliferative, or differentiated. However, MITF does not act alone. Here, we review literature on the transcription factors that co-regulate MITF-dependent genes. ChIP-seq studies have indicated that the transcription factors SOX10, YY1, and TFAP2A co-occupy subsets of regulatory elements bound by MITF in melanocytes. Analyses at single loci also support roles for LEF1, RB1, IRF4, and PAX3 acting in combination with MITF, while sequence motif analyses suggest that additional transcription factors colocalize with MITF at many melanocyte-specific regulatory elements. However, the precise biochemical functions of each of these MITF collaborators and their contributions to gene expression remain to be elucidated. Analogous to the transcriptional networks in morphogen-patterned tissues during embryogenesis, we anticipate that the level of MITF activity is controlled not only by the concentration of activated MITF, but also by additional transcription factors that either quantitatively or qualitatively influence the expression of MITF-target genes.

MITF—the first 25 years

“…Thus, while MITF is equal to other transcription factors in that it binds DNA to up-regulate or down-regulate transcription of its target genes, it is perhaps more than just equal in the sense that it is not dedicated to a specific response and rather coordinates a wide variety of cellular processes, unlike, for instance, the nuclear hormone receptors or the sterol response element-binding factor SREBP. Although additional transcription factors clearly play a critical role in melanocyte biology (Seberg et al 2017), given MITF's role in nonmelanocyte cell types and in regulating genes implicated in a wide range of cellular functions, this "most important transcription factor" has taken center stage in our understanding of melanocyte and melanoma biology. Even though a great deal of our knowledge of MITF regulation and function has come from work on melanoma, it should not be forgotten that MITF's physiological function is to control the development and differentiation of the cells in which it is expressed, including in melanocytes the response to UV irradiation.…”

Local genomic features predict the distinct and overlapping binding patterns of the bHLH‐Zip family oncoproteins MITF and MYC‐MAX

“…Likewise, our model found known colocalizing factors of MYC, YY1 (Shrivastava et al, ), and E2F1 (Leung, Ehmann, Giangrande, & Nevins, ), to be important features favoring the MYC‐MAX binding class over MITF. Although YY1 has also been shown to physically interact with MITF (Li et al, ; Seberg et al, ), our finding demonstrates that YY1 is more enriched in MYC‐MAX binding sites than MITF binding sites genomewide. Furthermore, we analyzed the distributions of the output value of the BDT model without bHLHL motifs for sites bound by only MITF, only MYC‐MAX, and both MITF and MYC‐MAX (Supporting Information Figure ).…”

“…SOX10, a TF previously reported to colocalize with MITF and regulate the cellular functions of melanocytes and melanoma (Laurette et al, ; Seberg, Van Otterloo, & Cornell, ), was the TF with the highest importance score among all non‐bHLH‐Zip TF motifs. SOX10 is a high‐mobility group TF expressed in the neural crest and neural crest‐derived cells.…”

“…We will subsequently describe a method using a new computational framework of boosted convolutional decision trees that learns the first three features from raw binding sequences of MITF and MYC-MAX. SOX10, a TF previously reported to colocalize with MITF and regulate the cellular functions of melanocytes and melanoma (Laurette et al, 2015;Seberg, Van Otterloo, & Cornell, 2017), was the TF with the highest importance score among all non-bHLH-Zip TF motifs.…”

Untitled

“…We also speculated, owing to the changes in expression of a cohort of MITF targets in response to CITED1 silencing, that CITED1 may even act as a co-factor for MITF. A recent review by Seberg et al has compared the cellular response to MITF as akin to morphogen pattern responses during development such that co-factors or 'collaborators' of MITF act to quantitatively or qualitatively affect MITF target gene expression (Seberg, Van Otterloo & Cornell, 2017). The study presented herein represents an advance on our previous work, and we believe, establishes CITED1 as one such MITF collaborator.…”