Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine

Abstract

ASXL1, ASXL2 and ASXL3 are epigenetic scaffolds for BAP1, EZH2, NCOA1, nuclear receptors and WTIP. Here, functional proteomics of the ASXL family members are reviewed with emphasis on mutation spectra, the ASXM2 domain and the plant homeodomain (PHD) finger. Copy number gains of ASXL1 occur in chromosome 20q11.2 duplication syndrome and cervical cancer. Truncation mutations of ASXLs occur in autism, Bohring–Opitz and related syndromes, hematological malignancies and solid tumors, such as prostate cancer, breast cancer and high-grade glioma, which are gain- or loss-of-function mutations. The ASXM2 domain is a binding module for androgen receptor and estrogen receptor α, while the PHD finger is a ligand of WTIP LIM domains and a putative chromatin-binding module. Phylogenetic analyses of 139 human PHD fingers revealed that ASXL PHD fingers cluster with those of BPTF, DIDO, ING1, KDM5A (JARID1A), KMT2E (MLL5), PHF2, PHF8 and PHF23. The cell context-dependent epigenetic code of ASXLs should be deciphered to develop therapeutics for human diseases.

Keywords:

• acute myeloid leukemia
• cardiovascular development
• colorectal cancer
• Forkhead-box transcription factor
• hepatocellular carcinoma
• melanoma
• microsatellite instability
• myelodysplastic syndrome
• ovarian cancer
• pancreatic cancer

Financial & competing interests disclosure

This study was supported in part by a grant-in-aid for the Knowledgebase Project from the Masaru Katoh’s Fund. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• ASXL family members are epigenetic scaffold proteins that are involved in nuclear receptor-dependent transcriptional regulation and EZH2-dependent transcriptional repression.

• Phylogenetic analyses of 139 human plant homeodomain (PHD) fingers revealed that ASXL PHD fingers are clustered with H3K4me3-binding PHD fingers, whereas ASXL2 PHD finger is utilized as a ligand for LIM2 and LIM3 domains of WTIP protein. Because PHD finger can function as binding pocket for chromatin components and surface epitope for protein–protein interaction domains, chromatin targets of the ASXL PHD fingers as well as proteins binding to the ASXL PHD fingers should be comprehensively characterized in the future.

• Germ-line and somatic copy number gains of ASXL1 occur in patients with chromosome 20q11.2 duplication syndrome and cervical cancer, respectively. Small-molecule inhibitors targeting the ASXL1 PHD finger could be developed as novel therapeutics for human diseases caused by copy number gain of the ASXL1 gene; however, the PHD finger inhibitors might elicit adverse effects similar to those caused by gain-of-function mutations of ASXL family members.

• Germ-line truncation mutations of ASXL1 occur in patients with Bohring–Opitz syndrome and of ASXL3 in patients with autism and Bohring–Opitz-related syndrome. Somatic truncation mutations of ASXLs occur in hematological malignancies and solid tumors. The epigenetic code of ASXL family members should be deciphered for the development of therapeutics for human diseases caused by ASXL truncation mutations.