Orchestrating epigenetics: a comprehensive review of the methyltransferase SETD6

Abstract

Transcription is regulated by an intricate and extensive network of regulatory factors that impinge upon target genes. This process involves crosstalk between a plethora of factors that include chromatin structure, transcription factors and posttranslational modifications (PTMs). Among PTMs, lysine methylation has emerged as a key transcription regulatory PTM that occurs on histone and non-histone proteins, and several enzymatic regulators of lysine methylation are attractive targets for disease intervention. SET domain-containing protein 6 (SETD6) is a mono-methyltransferase that promotes the methylation of multiple transcription factors and other proteins involved in the regulation of gene expression programs. Many of these SETD6 substrates, such as the canonical SETD6 substrate RELA, are linked to cellular pathways that are highly relevant to human health and disease. Furthermore, SETD6 regulates numerous cancerous phenotypes and guards cancer cells from apoptosis. In the past 15 years, our knowledge of SETD6 substrate methylation and the biological roles of this enzyme has grown immensely. Here we provide a comprehensive overview of SETD6 that will enhance our understanding of this enzyme's role in chromatin and in selective transcriptional control, the contextual biological roles of this enzyme, and the molecular mechanisms and pathways in which SETD6 is involved, and we highlight the major trends in the SETD6 field.

Fig. 1. Domain organization, structure, and function of SETD6.

a SETD6 is composed of two main functional domains: the SET domain (blue) and the Rubisco-substrate binding domain (orange). The residues forming the active site are depicted by red spheres. Isoform A has a 23-residue segment that is not present in isoform B. b The crystal structure of SETD6 (PDB: 3QXY) depicts the three-dimensional arrangement of the functional domains and the active site (same coloring as in a). The enlargement depicts the active site residues (red), S-adenosyl methionine (SAM) cofactor and substrate lysine; the latter two are colored on the basis of atoms (magenta, carbon; blue, nitrogen; red, oxygen; yellow, sulfur). c SETD6 uses the SAM cofactor to catalyze mono-methylation of substrate lysine residues.

Fig. 2. Expression of SETD6 in various tissues.

RNA expression of SETD6 in different human tissues (colored by common functional features). The y axis indicates normalized expression levels (nTPM). The data in the graph are from The Human Protein Atlas ‘Consensus Dataset’ for RNA expression (https://www.proteinatlas.org/).

Fig. 3. Differential expression of SETD6 in multiple cancers.

SETD6 expression data in TCGA tumors (red) and normal tumor-adjacent tissues (blue) were obtained from UCSC Xena (https://xenabrowser.net/). SETD6 expression data from both tissue types were taken from the ‘RSEM TPM’ expression dataset. BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical and endocervical cancer; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney clear cell carcinoma; KIRP, kidney papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; STAD, stomach adenocarcinoma; THYM, thymoma; THCA, thyroid carcinoma; UCEC, uterine corpus endometrioid carcinoma. These results shown here are based upon data generated by the TCGA Research Network (https://www.cancer.gov/tcga).

Fig. 4. SETD6 methylation of chromatin-bound transcription factors.

a SETD6 methylation of RELA recruits GLP, which deposits repressive H3-K9me1/2 marks and causes transcriptional repression of NF-κB target genes. b Methylation of TWIST1 on the LINC-PINT locus promotes the recruitment of EZH2 and the accumulation of H3-K27me3, which causes transcriptional repression. c SETD6 methylation of E2F1 promotes its binding to the SETD6 promotor. d BRD4 methylation blocks E2F1 recruitment to ribosomal target genes. Purple, SETD6; blue, SETD6 substrates; green, other proteins; red, methylation sites. The nucleosome icon was created in BioRender.com.

Fig. 5. SETD6 methylation of protein kinases.

a SETD6 methylation of PLK1 attenuates its protein kinase activity. b PAK4 methylation on chromatin increases its association with β-catenin, which promotes the transcription of Wnt/β-catenin target genes. The color coding is the same as in Fig. 4.

Fig. 6. Sequence commonalities among lysine-defined SETD6 substrates.

Substrates are classified into four categories based on whether they are a histone or non-histone substrate and whether methylation is known to occur in a physiological environment or is only known to occur in an in vitro context.