Jaya Krishnan, Ph.D.

In the Krishnan lab, we delve into the fascinating world of Astyanax mexicanus, commonly known as the blind Mexican cavefish. These fish live in environments with little light and nutrition. Our goal is to unravel their extraordinary survival strategies to gain insights for human health.

Surviving extreme habitats
Animals have adapted to survive very long periods of low nutrients, including hibernating mammals, migratory birds, and our favorite - cavefishes. Most of these organisms binge eat to store up large amounts of energy before periods of starvation, but don’t experience damaging effects from the excess. How do they manage this? Can we study them to better understand human metabolic diseases such as diabetes and obesity?

Unraveling cavefish mysteries
In the depths of subterranean caves, blind fish, Astyanax mexicanus, have evolved adaptations to conquer challenges of limited energy resources. We investigate how cavefish endure extended periods without food. My work has revealed that differences in gene regulation may hold the key to their resilience. My lab uses modern genetic and genomic tools to search for unique features contributing to their survival.

Our studies shed light on the evolutionary forces shaping cavefish physiology and draw a bridge to human health. Our mission is to extend our findings beyond the lab to pave the way for innovative approaches in treating metabolic disorders in humans.

Unraveling the genetic secrets of metabolism
In my lab, we are dedicated to understanding the genetic underpinnings of metabolism in Astyanax mexicanus, a unique species of cavefish that exhibit remarkable adaptations to metabolic challenges. Our research aims to shed light on the evolution of gene regulatory networks in these obese, yet metabolically healthy cave-dwelling fish, with the ultimate goal of gaining insights into metabolism and metabolic syndrome in humans.

The Astyanax advantage: nature's solutions to metabolic challenges
Metabolic syndrome encompasses a constellation of closely linked, heritable traits including hyperglycemia, excess adiposity, fatty liver and hypertension. With nearly 1 in 10 adults affected by diabetes and a third of the U.S. population grappling with obesity, there is an urgent need for a deeper understanding of the genetic factors at play. While numerous loci associated with metabolic disorders have been identified, the knowledge of protective alleles remains limited. Our lab harnesses the Astyanax mexicanus system to bridge this gap in knowledge.

Astyanax mexicanus resides in lightless, nutrient-scarce caves, facing seasonal limitations in food availability, leading to extended periods of starvation. Astonishingly, these cavefish have evolved adaptations that allow them to maintain high blood glucose levels, accumulate excess body fat and develop fatty liver without experiencing the harmful effects seen in humans such as inflammation and glucose toxicity. These protective mechanisms against metabolic syndrome-like features are absent in the surface-dwelling ancestral populations, making the Astyanax system an ideal genetic model to uncover nature's solutions for evading the detrimental effects of metabolic disorders.

We are interested in understanding the genetic basis of this phenotype and address three core questions:

• How do cavefish synthesize and store excess fat?
• How do they mobilize stored fat when faced with limited food resources?
• How do they mitigate the adverse effects of excess fat accumulation?

Building on previous studies, including my postdoctoral work, we have observed significant divergence in metabolic pathways between cavefish and surface fish, driven by both coding and non-coding genomic changes. Using state-of-the-art genomic techniques, such as ATAC-seq, ChIP-seq, promoter capture Hi-C, and Massively parallel reporter assays, we aim to identify key genetic variations and physiological pathways driving this divergence. Additionally, we leverage liver-derived cell lines from both surface fish and cavefish as powerful in vitro systems for molecular dissection of metabolic traits.

Education
B.Sc., Biochemistry (Honors), University of Delhi, 2007
M.Sc., Department of Genetics, University of Delhi, South Campus, India, 2009
Ph.D., Center for Cellular and Molecular Biology, India, Dr. Rakesh Mishra, 2009-2015,
Postdoctoral training, Stowers Institute for Medical Research, Kansas City, Dr. Nicolas Rohner, 2015-2022

Awards and Honors
Rotary Club Scholarship, 2007-08
Qualified Graduate Aptitude Test in Engineering exam for pursuing Ph.D., 2008
Full-time CSIR fellowship from the Govt. of India for 5 years, 2009
Travel grant by CICS, Govt. of India, 2014
Travel grant by CSIR, Govt. of India, 2014
Travel grant by the DST, Govt. of India, 2014
KV Rao Young Scientist Award for my Ph.D. research, 2015
Travel fellowship, Society for Developmental Biology, 2018
Best Poster Award, second prize, Young Investigator Science Retreat 2018, Stowers Institute for Medical Research, 2018
Hilde Mangold Postdoctoral Symposium Award, 80th Annual Society for Developmental Biology Meeting, 2021

Joined OMRF scientific staff in 2023

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Selected Publications

Krishnan, J., Wang, Y., Kenzior, O., Hassan, H., Olsen, L., Tsuchiya, D., Kenzior, A., Peuss, R., Xiong, S., Wang, Y., et al. (2022). Liver-derived cell lines from cavefish Astyanax mexicanus as an in vitro model for studying metabolic adaptation. Sci Rep 12, 10115.

Krishnan, J., Seidel, C.W., Zhang, N., Singh, N.P., VanCampen, J., Peuss, R., Xiong, S., Kenzior, A., Li, H., Conaway, J.W., et al. (2022). Genome-wide analysis of cis-regulatory changes underlying metabolic adaptation of cavefish. Nat Genet 54, 684-693.

Krishnan, J.*, Persons, J.L.*, Peuss, R.*, Hassan, H., Kenzior, A., Xiong, S., Olsen, L., Maldonado, E., Kowalko, J.E., and Rohner, N. (2020). Comparative transcriptome analysis of wild and lab populations of Astyanax mexicanus uncovers differential effects of environment and morphotype on gene expression. J Exp Zool B Mol Dev Evol. Nov;334(7-8):530-539 (* Equal contribution)

Krishnan, J., and Rohner, N. (2019). Sweet fish: Fish models for the study of hyperglycemia and diabetes. J Diabetes 11, 193-203 (Review article)

Kumar, R.P.*, Krishnan, J.*, Pratap Singh, N., Singh, L., and Mishra, R.K. (2013). GATA simple sequence repeats function as enhancer blocker boundaries. Nat Commun 4, 1844. (* Equal contribution)

Genes & Human Disease Research Program, MS 57
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104

E-mail: Jaya-Krishnan@omrf.org

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Manu Tomar
Postdoctoral Scientist

Tyler Guzman
Research Technician

Sumedha Mukhi
Research Technician III

Suzy Collins
Project Coordinator II