Understanding the molecular choreography in the nucleus of a cell.
I am a cell and developmental biologist studying how the nucleus builds itself in space and time, and how this dynamic architecture gives rise to cellular identity and function. I focus on how nuclear organization emerges, how it is remodeled during development, and how its failure contributes to disease.
To uncover these principles, I combine molecular biology, biophysics, genetics, and imaging across length scales, from live-cell optical microscopy to in situ cryo-electron microscopy, in both cell culture and model organisms. This allows me to connect molecular events inside the nucleus to their consequences for the cell and the whole organism.
Cellular function arises from molecules finding the right place at the right time. The nucleus is a remarkable example of this challenge, where millions of molecules precisely self-organize into dynamic compartments without membrane boundaries to coordinate gene expression, ribosome biogenesis, DNA replication, genome maintenance, and RNA processing. Understanding how cells build and remodel this extraordinary spatial organization is fundamental to understanding development, adaptation, aging, and disease.
I am a Research Scientist in the Department of Molecular and Cell Biology at the University of California, Berkeley. I received my Ph.D. in Cell and Developmental Biology from Weill Cornell Graduate School of Medical Sciences, New York, and my integrated M.S./B.S. in Biological Sciences from BITS Pilani, India.
Over two meters of DNA must be organized inside a single nucleus only a few microns across. Moreover, this DNA must be continually regulated and remodeled to dictate the cell's destiny. These are the questions that drive my research: how does the nucleus' entirely membrane-less internal organization emerge? How do its different sub-compartments work together? And what happens when this coordination breaks down?
I focus on the nucleolus and heterochromatin, two of the largest nuclear compartments, responsible for building the cell's protein synthesis machinery and safeguarding the genome, respectively. Through this work, I aim to reveal the principles that govern how nuclear sub-compartments coordinate (or fail to) as an integrated system during development and disease.
My scientific journey has taken me across continents, disciplines, model systems, and imaging modalities. Hover over a marker, or tap on mobile, to explore each stop along the way.
Each stop on the map marks a place I trained and a question I chased.
Science is as much about people as it is about discovery.
Throughout my career, I've enjoyed leading initiatives that help early-career researchers find kinship and exchange ideas. At UC Berkeley, I founded the MCB Postdoctoral Research Showcase, now an annual department-wide event in its fifth year that celebrates postdoctoral research. I also led BITS2MSPhD, an alumni mentorship initiative that has helped students from my undergraduate institution pursue graduate training around the world. Earlier, as Biology Coordinator at BITS Pilani, I organized student teams and their research presentations for APOGEE, the institute's annual techfest.
Mentoring has been another rewarding part of my career. I've had the opportunity to work with undergraduate and graduate students, at different stages of their training, and I enjoy helping them develop as independent experimental scientists.
How does a nucleus build itself?
I study how molecular interactions organize the nucleus into a dynamic, integrated, and functional system. I use the nucleolus and heterochromatin, two large neighboring compartments, to uncover how nuclear structures assemble, interact, and remodel.
During my postdoctoral work, I discovered a molecular linker that connects these membrane-less compartments. Combining Drosophila genetics, live imaging, and physical theory, I showed that changing the strength of their interactions can reorganize the nucleus in 3D.
My research now asks how these organizing mechanisms are regulated across cell states, and how they connect nuclear structure to genome function and ribosome production in development and disease.
Visualizing ribosome biogenesis inside human cells
Ribosomes are remarkable molecular machines that make every protein in a cell. They are themselves made through a complex assembly line that begins in the nucleolus, an organelle at the center of my postdoctoral research. In the Lucas Lab, I am learning cryo-electron microscopy and two-dimensional template matching to visualize the choreography of ribosome assembly inside the nucleus of human cells at near-atomic resolution.
When loss of repeat silencing activates innate immunity
DNA methylation keeps repetitive regions of the genome silent, but the consequences of losing this regulation in a developing animal were unclear. During my Ph.D., I generated a zebrafish model of ICF syndrome, a rare disorder marked by severe loss of DNA methylation at pericentromeric satellite repeats.
Using this model, I discovered that hypomethylated satellite repeats become aberrantly transcribed and these satellite RNAs activate an interferon response. This work connected the loss of an epigenetic mark at repetitive DNA to an organism-wide innate immune response, revealing how epigenetic dysregulation can manifest in disease.
More than the sum of its parts
I enjoy collaborations that combine different fields or approaches to generate new ways of understanding a biological problem. Communicating and translating across disciplines has been among the more rewarding parts of my scientific journey.
With the Safran Group, integrating my experiments with physical theory of how immiscible liquids interact was essential to understanding how the nucleolus and heterochromatin organize within the nucleus. I have also brought my quantitative imaging and chromatin biology expertise to work with the Whiteman Group on sensory evolution, and with the Botchan Group on how altered protein interactions affect heterochromatin function.
Hierarchical interactions between nucleolar and heterochromatin condensates are mediated by a dual-affinity protein
Read the paper →ORC binding to Heterochromatin Protein 1 through intrinsically disordered regions is required for heterochromatin structure and function
Preprint →Odorant receptors mediating avoidance of toxic mustard oils in Drosophila melanogaster are expanded in herbivorous relatives
Link →Alternative splicing in TRPA1 drives sensory adaptation to electrophiles in drosophilids
Preprint →The maternal to zygotic transition regulates genome-wide heterochromatin establishment in the zebrafish embryo
Link →Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome
Read the paper →The notochord breaks bilateral symmetry by controlling cell shapes in the zebrafish laterality organ
Link →Say hello.
Always glad to talk science, collaborations, or new opportunities. The fastest way to reach me is email.
srajshekar@berkeley.edu