Featured Scientist: Dr. Hank Qi

OneArray^® Research In Focus: Epigenetic Regulation

Dr. Hank Qi has been solving biochemical pathway puzzles involved in cancer as well as other diseases for the past 20 years of his career. His most recent work completed in Dr. Yang Shi's laboratory from Harvard Medical School adds to a growing wealth of evidence for the importance of epigenetic regulation during development. Modifications of histone residues serve as a major element in epigenetic regulation. "Histone methylation dynamics [in particular] play an important role in transcription regulation, genomic stability and DNA replication. Mis-regulation of histone methylation by mal-functioned histone methylases or demethylase leads to developmental defects and disease conditions including cancer development" says Dr. Hank Qi.

In his paper published in Nature (Nature. 2010 Jul 22;466(7305):503-7), Dr. Qi describes the discovery of demethylase, PHF8 (PHD finger protein 8), which is commonly mutated in X-linked mental retardation (XLMR) patients. XLMR is generally accompanied with defects in craniofacial, muscular and hematopoietic development as well as intellectual disability. Current treatment options are limited to correction of the physical abnormality using surgical procedures that seal the patient's lip and cleft regions. Decreased neurological capabilities remain a permanent problem. Using a combination of microarray-based gene expression profiling (Phalanx Biotech Group OneArray® Microarray) and Chip-Seq techniques, Dr. Qi identified direct target genes of PHF8 demethylase in hopes to tease out the intricate pathways responsible for PHF8 function. In an elegant experiment using zebrafish model, PHF8 is shown to regulate brain and craniofacial development via MSX1/zMSXb, an important gate-keeper in several signaling pathways involved in craniofacial and neuro-development. Other developmentally important signaling networks such as the retinoid acid and Notch pathways were also targeted by PHF8, suggesting its involvement during development is complex and may have cascading effects with broad implications.

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Results from Dr. Qi's study will be valuable in developing therapeutics for diseases resulted from abnormal histone methylation event. Understanding its upstream variables will also aid in creating preventative measures for XLMR, because nutrition and other environmental cues have been shown to affect demethylase activity and are correlated with XLMR prevalence. Another area active interest in histone methylation sprouted from observations made in breast, head and neck cancers. Evidence show punctuated changes in demethylase activity in both early and metastatic stages of various cancers, implicating histone methylation during the initiation and progression phases of oncogenesis. Though the causative relationship between histone demethylase and carcinogenesis is still under investigation, Dr. Qi is hopeful we will be able to exploit our knowledge of histone methylation process to design therapeutic targets and cancer biomarkers. While the rules of histone acetylation are clear and predictable (deacetylation causes heterochromatic conformation and turns genes "OFF", and acetylation causes euchromatin conformation and turns genes "ON"), histone methylation is a rather functionally flexible event. "It can act as both a positive and negative regulator of gene transcription, depending on co-factors involved on-site" explains Dr. Qi. In addition, histone methylase exerts target substrate specificity via its enzymatic domain, making it a good candidate for potential therapeutic target possibly with fewer side effects. Indeed, results from early-stage development of inhibitory agents for histone methylation seem positive in contrast to histone acetylation inhibitors, which unfortunately have shown to be non-specific in most cases. It will be interesting to follow up on detailed mechanistic studies for these histone methylation inhibitors, and more importantly how well they perform in clinical trials.