Epigenetic Regulation of Development & Disease

We are particularly interested in studying how cell fates are specified during development and misspecified in disease.

In eukaryotes, transcriptional regulation occurs on DNA that is packaged in chromatin. The packaging of DNA into nucleosomes provides a basic layer of repression by reducing access to DNA. Additional modulation of chromatin structure could further regulate access for DNA-binding factors and, therefore, potentially occur upstream of sequence-based regulation.

Recently, several molecular pathways that modify histones and DNA in a dynamic manner have been found. This dynamic modification defines a cell type specific transcriptome and its identity.The regulatory sequences (e.g. promoters, enhancers) in eukaryotic genomes show characteristic patterns of histone modifications that associate with active or inactive state of the linked gene. These modifications are heritable, but do not involve changes in the DNA sequence and therefore are referred to as ‘epigenetic’ modifications. One of the main functions of epigenetic modifications is to regulate the accessibility of DNA for regulatory factors and/or establish higher-order chromatin structures, which would be either permissive or restrictive for transcription. Thus, while genetic information provides the basic code for cellular contents, the epigenetic information defines how, when and where this code has to be used. While proper epigenetic patterns are crucial for cell fate specification during development, mis-regulation of the epigenome has been implicated in a number of complex diseases including cancer.

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The research in our lab aims to achieve an integrated molecular and systems-level understanding of transcriptional reprogramming via epigenetic machinery and regulatory factors. This process defines cell type identity during development and can be altered in diseases such as cancer.  We employ a multidisciplinary approach combining cutting-edge epigenetics and genomics together with computational biology tools in sophisticated and defined models of cellular differentiation and carcinogenesis. Our primary research interests include:

•    Signalling to Chromatin Crosstalk in Gene Regulation: Do cells respond to extracellular cues by modulating epigenetic signature in the genome, which in turn is translated to changes in gene expression? 
   
•    Transcription Factors and Lineage Specification: How do lineage-specific transcription factors contribute to acquisition and maintenance of cell fate?

•    Epigenomics of Cell Type Specification: Could we employ high-throughput epigenomics approaches to uncover epigenetic principles underlying a cell type identity?

•    Epigenetic Regulation of Neurogenesis: Are there still unidentified proteins in the mammalian genome that function in epigenetic regulation of gene transcription? Could we characterize the function of some of these proteins in neuronal development?

•    Chromatin and Cancer: Could we identify new factors that function on chromatin in driving aberrant transcription program during metastasis?

•    Systems Biology of Gene Regulatory Networks:
Could we apply mathematical modelling on genome-wide datasets to generate general principles of how epigenetic regulators and transcription factors function to elicit specific transcriptional responses during development and how this is altered in disease?

Vijay is a RISE1 (Research Integrating Systems Biology and Epigenetics) member of the EpiGeneSys network of scientists.