DASGUPTA LABORATORY
Recreating the lost RNA World of primordial life
Illuminating the hidden RNA World of modern life
RESEARCH GOALS
We want to understand RNA at its most fundamental - its past in ushering the Origin of life by converting chemistry to biology, its present roles in biology, and its future applications as tools to understand biology.
RNA plays crucial roles in biology and its significance continues to grow as new discoveries are made. The DasGupta lab will focus on a holistic exploration of RNA. We will investigate RNA structure, function, and evolution. By studying its structure, we will explore how its three-dimensional shape influences its function and interactions with other biomolecules. We are deeply interested in a special class of RNA molecules that show catalytic activity, called ribozymes. We will use biochemistry, high-throughput sequencing, and structural biology approaches to understand how ribozymes catalyze chemical reactions when most RNAs do not. We are also interested in the evolutionary processes that allow RNA molecules to adapt to new functions like enzyme catalysis or ligand binding (in aptamers). We will routinely use combinatorial techniques like in vitro selection and directed evolution to discover RNAs de novo that perform functions not found in biology.
In addition to its many biological roles, RNA bears a profound weight of biological history. It is widely accepted that the earliest forms of life on Earth (~3.8 bya) used RNA to constitute their genomes and as enzymes. Understanding the biochemical capabilities of RNA is therefore, crucial for unraveling the mysteries surrounding life's origins and advancing our knowledge of early evolutionary processes. We aim to create synthetic models of the earliest cells that show life-like behaviors such as growth, division, competition, and ultimately Darwinian evolution to understand how life emerged from nonliving matter. These studies will reveal fundamental physical and chemical principles underlying biology. We are also invested in using evolutionary approaches to develop RNA-based technologies to probe largely unexplored areas of RNA biology. This includes generating reagents to interrogate the biologies of RNA cleavage and non-canonical RNA capping, and generating aptamer-based biosensors. In the future, we hope to expand our research into studying non-natural nucleic acids.
The origin of life is one of the hardest problems in science. How did a chaotic collection of chemicals assemble into the organized life we see all around us? We think RNA holds the clue to this mysterious transmutation of Chemistry to Biology. RNA has a unique ability to carry genetic information and catalyze chemical reactions, which led to the formulation of the RNA World hypothesis, which posits that primordial life used RNA to constitute its genomes and as enzymes (ribozymes). We aim to build models of RNA-based primordial cellular life that exhibit life-like properties such as replication, growth, division, competition, and evolution. Let there be Life!
The Hidden RNA World
RNA plays key roles in nearly all cellular processes. RNA biology has been revolutionized by next-generation sequencing (NGS), allowing us to look at thousands of RNAs at once. During library preparation for NGS, target RNAs are ligated to sequencing adapters, reverse transcribed, and PCR amplified. Adapter ligation requires the target RNAs to contain 5' monophosphate groups and 3' hydroxyl groups making RNAs with terminal modifications incompatible with NGS. Consequently, cellular RNAs containing modified termini remain hidden, and the related metabolic pathways remain undiscovered. We aim to develop a suite of catalytic RNA reagents to capture and sequence RNAs containing specific 5′ and 3′ modifications, with unprecedented specificity. These new technologies will illuminate hidden portions of cellular transcriptomes, generating new knowledge about their architectures, biogenesis, and functions.