Overview


 


The Souroullas Lab is studying the role of epigenetic mechanisms during cancer formation, with a specific interest in B cell lymphoma and melanoma. 

Recent next generation sequencing studies have identified mutations in many epigenetic factors in multiple cancers.  The reversible nature of these proteins presents us with an opportunity in translational medicine.  Understanding the phenotypic and molecular consequences of epigenetic dysregulation during carcinogenesis remains a challenge, but it is critical in developing more effective therapeutic strategies.  Towards that end, our lab combines the use of genetically engineered mouse models with epigenetic, molecular, biochemical, and pharmacological methods to study how mutations in epigenetic factors promote the development of cancer.

What is epigenetics?


Traditional genetics suggest that our DNA determines our inherited traits, from our physical appearance to the molecular mechanisms that drive cellular processes.  DNA, the 3-billion-long sequence that makes up our genome, is made up of a sequence of only four bases (C, A, G, T), which encode the ~30,000 genes in the genome.  Variations in the DNA sequence is what makes us different from other species and also unique from one another.  Errors in this sequence is also what gives rise to genetic disorders and diseases such as cancer.

The word epigenetics starts with the Greek prefix επι- which means “over”, “around” or “above”, which suggests that there are features over and above the genetic code that also affect how it functions and is interpreted.   Strictly speaking, the term epigenetics suggests that these features must be inherited across multiple cell divisions, contribute to genetic traits and be inheritable across generations.  However, the term epigenetics is more loosely used to include any post translational modification to histones of the DNA itself that regulates transcription.  For example, one modification involves the addition of a methyl group to DNA bases, referred to as DNA methylation.  Another epigenetic mark involves the addition of chemical groups on the histone proteins, which make up the packaging component of the DNA.  These modifications can determine whether a gene is turned “on” or “off”, which can in turn determine cell identify, growth and proliferation; important cellular functions commonly altered in cancer.

Epigenetics and Cancer


Epigenetic regulation is a very dynamic process which involves three main components: (1) Writers: These are proteins which catalyze the addition of chemical groups on the DNA or chromatin, (2) Readers:  Proteins which recognize these chemical groups, interact with them, interpret them and transmit further downstream signals.  (3) Erasers:  Proteins that recognize these marks and catalyze their removal.  All these processes together regulate fundamental processes of the cell, such as DNA transcription, replication, repair, cell identity, growth and proliferation; these cellular processes are also implicated in cancer, suggesting that epigenetics must play an important role during cancer development.

 

Figure 1.  Dynamic epigenetic regulation of cellular processes by epigenetic readerswriters and erasers.

The role of PRC2 and EZH2 in cancer


Our lab is particularly interested in the role of the Polycomb Repressive Complex 2 (PRC2) in cancer.  PRC2 is an epigenetic writer, which establishes the repressive epigenetic mark histone 3 lysine 27 trimethylation (H3K27me3), resulting in silencing of gene expression.  The catalytic subunit of the PRC2 complex is EZH2 (Enhancer of Zeste Homolog 2).  EZH2 was initially thought to be a tumor-suppressor since loss-of-function events were observed in Myelodysplastic syndrome (MDS), Acute Myeloid Leukemia (AML) and T-cell Acute Lymphoblastic Leukemia (T-ALL).  However, more recent next-generation sequencing studies have also identified activating point mutations and amplifications of EZH2 in a wide range of cancers (Figure 2), suggesting that EZH2 also functions as an oncogene.  Furthermore, mutations within the SET domain of EZH2 (e.g. Tyr 641) appear to behave in a neomorphic manner in B cell lymphomas and melanoma, further complicating the role of EZH2 and our understanding of its role in cancer.  These data suggest that the role of EZH2 in cancer is cell type-dependent, however, the underlying oncogenic mechanisms mediated by EZH2 point mutations or other genetic aberrations are not fully elucidated and are critical in understanding its role during malignant transformation. 

 

Figure 2.  Genetic aberrations of EZH2 in human cancers.

Research Goals


Our lab is interested in exploring the above mechanisms using genetically engineered mouse models in combination with molecular, biochemical, and pharmacological approaches.  Overall, our goal, is to explore how epigenetic mechanisms interact under homeostatic conditions, how those interactions are perturbed in cancer, how they interact with other oncogenic events and how we can take advantage of this knowledge to design more effective therapeutic strategies.  Current projects in the lab include:

  •  Investigation of the underlying molecular mechanisms that result in the neomorphic properties of the EZH2 mutations observed in B cell lymphoma and melanoma,
  • Understand the downstream mechanisms responsible for the oncogenesis and disease pathogenesis in EZH2-mutant lymphoma and melanoma, and
  • Unravel the interplay between the various epigenetic modifications during cancer development by studying genetic interactions of EZH2 with other chromatin-modifying factors

 

 

Figure 3.  Schematic of various epigenetic mechanisms and interactions of the PRC2 complex, which regulate chromatin dynamics, accessibility to chromatin and gene expression


 

References/Credits:

Model of PRC2 structure from Jiao et al, Science, 2015
Home page images from Souroullas et al, Nature Medicine, 2016
Landscape of EZH2 genetic events in cancers, data analysis through cBioportal