Biology subjects

Goding, C.

Publications and source records attributed to Goding, C..

3 recordsLinked to original sources

bioRxiv2025

SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma cells

Aberrant transcriptional programs mediate malignant transformation of melanoma, the most aggressive form of skin cancer. The lysine methyltransferase SETD6 has been implicated in regulating transcription, cell adhesion, migration, and other processes in various cancers, however its role in melanoma remains unexplored. We recently reported that SETD6 mono-methylates the BRD4 at K99 to selectively regulate transcription of genes involved in mRNA translation. Here, we observed that BRD4 methylation at K99 by SETD6 occurs in melanoma cells. Knockout of SETD6 or a point mutation at BRD4-K99 disrupts BRD4 genomic occupancy. In addition, we show that SETD6 interacts with MITF, a master transcription factor in melanocytes and melanoma, and influences the genomic distribution of MITF. Mechanistically, we uncover a novel chromatin-localized interaction between BRD4 and MITF in melanoma. Our data suggest that BRD4 binds MITF in melanoma cells and that this interaction is dependent on both SETD6-mediated methylation of BRD4 and MITF acetylation. This chromatin complex plays a pivotal role in selective recruitment of BRD4 and MITF to different genomic loci in melanoma cells.

molecular biology↗

bioRxiv2023

Loss of MC1R signaling implicates TBX3 in pheomelanogenesis and melanoma predisposition

The human Red Hair Color (RHC) trait is caused by increased pheomelanin (red-yellow) and reduced eumelanin (black-brown) pigment in skin and hair due to diminished melanocortin 1 receptor (MC1R) function. In addition, individuals harboring the RHC trait are predisposed to melanoma development. While MC1R variants have been established as causative of RHC and are a well-defined risk factor for melanoma, it remains unclear mechanistically why decreased MC1R signaling alters pigmentation and increases melanoma susceptibility. Here, we use single-cell RNA-sequencing (scRNA-seq) of melanocytes isolated from RHC mouse models to reveal a Pheomelanin Gene Signature (PGS) comprising genes implicated in melanogenesis and oncogenic transformation. We show that TBX3, a well-known anti-senescence transcription factor implicated in melanoma progression, is part of the PGS and binds both E-box and T-box elements to regulate genes associated with melanogenesis and senescence bypass. Our results provide key insights into mechanisms by which MC1R signaling regulates pigmentation and how individuals with the RHC phenotype are predisposed to melanoma.

genetics↗

bioRxiv2021

BRN2 is a non-canonical melanoma tumor-suppressor

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, we show that BRN2 haplo-insufficiency is sufficient to promote melanoma initiation and metastasis, acting as a non-canonical tumor suppressor. Mechanistically, BRN2 directly modulates PTEN expression, and PI3K signaling, to drive tumor initiation and progression. Collectively our results reveal that somatic deletion of one BRN2 allele elicits melanoma initiation and progression. SIGNIFICANCEHere, we report frequent mono-allelic loss of the transcription factor BRN2 in human cutaneous melanoma metastases. We developed a mouse model for Brn2-deficient melanoma based on the most common alterations (BrafV600E and Pten loss) in human melanoma and established the role of Brn2 as a functional regulator of tumor initiation, tumor growth, and the formation of metastases in vivo. Mechanistically, BRN2 loss increases PI3K-signaling through PTEN repression, either via MITF induction or not. Overall, we describe a novel tumor suppressor of high prevalence in human melanoma that regulates several steps of in vivo melanomagenesis through two previously unknown molecular mechanisms.

cancer biology↗