My lab is currently focused on epigenetic and cancers. Most particularly, we are interested in understanding the histone code and its implications in diseases, especially cancers. It is a really fascinating research areas.

Cancer initiation and progression are controlled by both genetic and epigenetic events. Both genetic and epigenetic alterations of transcriptional co-regulators are key features in carcinogenesis onset with aberrant gene functions and changes in gene expression levels.

Histone modifications along with other epigenetic mechanisms such as DNA methylation maintain gene activity states and are key in regulating a wide range of cellular processes. Alterations and deregulations in the function of enzymes that modify histones alter the array and levels of histone marks and ultimately affect the control of chromatin-based processes. It leads to dramatic changes in gene expression profiles, which eventually contribute to oncogenic transformation and the development of cancer.

Histones are the stage of multiple post-translational modifications. Specific residues on histones H2A / H2B, H3 and H4 can be modified by methylation (Lysine / Arginine), acetylation (Lysine), citrullination (Arginine), phosphorylation (Serine / Threonine), ubiquitination (Lysine), sumoylation (Lysine), ADP-ribosylation (Lysine), butyrylation (Lysine), propionylation (Lysine) and glycosylation (Serine / Threonine).

Amongst the array of covalent histone modifications, lysine methylation is one of the prominent signaling pathway in chromatin-regulatory mechanism. Lysine-histone methyltransferases (HMTases) are transcriptional co-regulators that target specific lysines on H3 and H4, and can transfer up to three methyl groups (Kme1, Kme2, and Kme3) on histone tails. Lysine methylation, or any of the other histone modifications, can have both activating and repressive functions on transcription events. All the covalent histone modifications contribute to finely regulating the diverse activities associated with the chromatin and may be referred as a language of covalent histone modifications or histone code that is still obscure.

One fascinating aspect of the regulation of the transcription lies in the ballet between histones modifiers “readers” and “writers”, both being regulated leading to various physiological output based on the cellular context. This appends complexity to our current limited understanding of gene transcription and its implication in human diseases.

I had great time attending the 2011 edition of the America Association for Cancer research satellite meeting “Molecular Targets and Cancer Therapeutics 2011″ held in San-Francisco. I am very pleased with the overall quality of the meeting and the data presented. It was a fantastic opportunity to expand my background, present our research and connect with various individuals for future collaborative work. Several companies have shown great interest in our work especially regarding our current studies on histone methyl transferase and their specific and selective inhibitors. The poster I presented can be downloaded here (PDF). Below, is the abstract submitted to the meeting.

Background: The nuclear receptor binding SET domain (NSD) protein is a family of three histone-lysine N-methyltransferase (HMTase), NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 that are critical in maintaining the chromatin integrity. NSD1 methylates H3K36 and H4K20 and is associated with acute myeloid leukemia, multiple myeloma, and lung cancer. The NSD1-NUP98 translocation plays a significant role in childhood acute myeloid leukemia with NUP98-NSD1 being an active H3K36 methylase. NSD1 is amplified in multiple myeloma, lung cancer, neuroblastomas and glioblastomas. NSD2 methylates H3K36 and is linked to prostate cancer and multiple myeloma. Over expression of NSD2 in myeloma cells leads to aberrantly high levels of H3K36 di-methylation, accompanied by a decrease in H3K27 methylation. NSD2 is found over expressed in fifteen different cancers and is associated with tumor aggressiveness or prognosis in most types of cancers. NSD3 methylates H3K36 and is associated with both lung and breast cancers along with the acute myeloid leukemia. The amplification of either NSD1 or NSD2 triggers the cellular transformation. NSD3 is found amplified in breast cancer cell lines and primary breast carcinomas. Reducing NSDs activity through specific and selective lysine-HMTase inhibitors appears promising to help suppressing cancer growth.

Little is known about the NSD pathways and our understanding of the histone Lysine-HMTase mechanism is partial. The SET domain of NSD1 has specific mechanisms to recognize histone marks unlike other HMTase. The precise catalytic activities of the NSDs are obscure and discrepancies exist hindering progress in understanding their exact biological functions and pathways in cancer pathogenesis. In this study, we explored the in vitro catalytic activities on histone substrates to understand the substrate recognition and to pave the way for the design of selective and specific NSD inhibitors usable in cancer therapies.

Methods: We used both biochemical and computational methods to understand the substrates recognition by the NSDs and to investigate the structural mechanisms happening in the SET domain during the binding of histone tails.

Results: A key regulatory and a recognition mechanism is driven by the flexibility of a loop at the interface of the SET and postSET region who rotates ~45° and translated 7Å opening the SET domain for the binding of the peptide ligand. This regulatory loop acts as a seat belt for the ligand and contributes to the discrimination and the substrate specificity. In vitro, The SET domain of the NSDs favor H3 recognition and are able to methylate a range of substrate. To reconcile with the in vivo activities previously reported on H3K36 and H4K20, we propose a cross-talk mechanism controlling the substrate recognition.