Research Interests
Roughly two meters of genomic material are crammed inside a microscopically small nuclear space in a non-random fashion while still being accessible for its function. Chromatin conformation capture (3C/HiC) technologies have been useful in understanding this complex three-dimensional architecture with intricate details in different cells and disease conditions. Genome organization involves a combination of genetic and structural elements to form a complex landscape of chromatin contacts. This multifaceted folding of chromatin in three-dimensional space has emerged as a potential key regulator of genome function, contributing to the development and cellular identity. In conditions where cellular functions are impaired, including in cancer cells, the higher-order genome organization is disrupted, leading to the inactivation of tumor suppressors or activation of oncogenes. However, understanding the functionality associated with the 3D genome remains a challenge, as the internal structures and elements contributing to chromatin organization within the nucleus are yet to be understood. Using integrated genomics approaches, we aim to decode the mechanisms responsible for chromatin folding in three-dimensional space and how these features contribute to cellular differentiation, cellular identity, and are deregulated during disease conditions.
Our working hypothesis is that our genomic DNA is dynamic and undergoes regular deformation, resulting in supercoiling, bending, and twisting of its helical structure. These mechanical and physical properties of chromatin, along with alternative DNA structures such as cruciform, Z-DNA, and H-DNA, play a crucial role in dictating genome organization.
Based on our hypothesis, our research focuses on the following major themes:
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(i) DNA topological changes during embryogenesis:
The essential aspect of mammalian development is the fusion of two differentiated and mature cells - egg and sperm cells - to form a zygote. These cells' chromatin and epigenetic program are reset to give rise to a totipotent embryo. The factors and mechanisms responsible for triggering chromatin reprogramming during embryo formation are largely unknown. Using the mouse model system, we aim to decode the genome memory passed on from parental cells that will trigger and establish Zygote Genome Activation (ZGA).
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(ii) Cellular identity during differentiation:
Cellular identity during differentiation is regulated by a complex interplay of genetic and epigenetic mechanisms, as well as changes in morphology and function, which allow cells to acquire specialized identities and perform specific functions within the organism. This process is tightly regulated and involves the activation and repression of specific genes, as well as changes in genome organization and function. Using mouse embryonic stem cells, we aim to study the structural changes and their consequences occurring at the genome level during differentiation.
(iii) DNA topology's role in dictating RNA splicing and transcription control:
The winding and unwinding of DNA during RNA splicing is an important factor that can influence the accessibility of splicing factors, the efficiency of splicing, and the specificity of splicing patterns. Chromatin-architectural proteins are shown to regulate alternative splicing of specific genes involved in cell proliferation, apoptosis, and differentiation. Using mouse and cancer cells, we aim to understand how DNA topology-related events can regulate transcription and RNA splicing.
(iv) Helicobacter pylori-induced gastric carcinogenesis and its impact on host genome architecture:
Helicobacter pylori infection is the primary root cause of gastric cancer, the third leading cause of cancer mortality. Roughly fifty percent of the world's population is estimated to be infected with H. pylori. Yet, it is still unknown why only a subset of the population develops gastric cancer while others do not. We aim to understand chromatin conformation changes occurring upon H. pylori infection and explore its potential mechanisms in altering nuclear architecture and dysregulation during cancer progression. Using the gastric cancer model, we aim to understand the impact of H. pylori on host chromosome structure and genome organization.