DCMB Seminar Series pres.
DCMB Seminar - Neurons in pathology through the lens of multi-omics and data analytics
Shankar Subramaniam, Ph.D. (UCSD)
Advances in stem cell engineering, omics technologies and data sciences offer a unique scope for deciphering the myriad ways molecular circuits dysfunction in pathologies of the brain. Recently, we have developed and explored iPSC-derived neurons from familial Alzheimer’s disease patients using a systems-level, multi-omics approach, identifying disease-related endotypes, which are commonly dysregulated in patient-derived neurons and patient brain tissue alike. By integrating RNA-Seq, ATAC-Seq, and ChIP-Seq approaches, we determined that the defining disease-causing mechanism of AD is de-differentiation of neurons, driven primarily through the REST-mediated repression of neuronal lineage specification gene programs and the activation of cell cycle reentry and non-specific germ layer precursor gene programs concomitant with modifications in chromatin accessibility. Strikingly, our reanalysis of previously-generated AD-patient brain tissue showed similar enrichment of neuronal repression and de-differentiation mechanisms. Surprisingly, our earlier work on glioblastoma also showed de-differentiation and initiation of some of the shared diseased endotypes as common features. We postulate that de-differentiation and reprogramming are hallmark mechanisms of numerous pathologies, arguably genetically evolved to serve as protection mechanisms.
Acknowledgements: This work was done in collaboration with the Laboratory of Dr. Wagner and his colleagues.
Caldwell AB, Liu Q, Schroth GP, Tanzi RE, Galasko DR, Yuan SH, Wagner SL, Subramaniam S. Dedifferentiation orchestrated through remodeling of the chromatin landscape defines PSEN1 mutation-induced Alzheimer's Disease. 2019 (under revision in Nature) Available from: https://www.biorxiv.org/content/10.1101/531202v1.
Friedmann-Morvinski D, Bhargava V, Gupta S, Verma IM, Subramaniam S. Identification of therapeutic targets for glioblastoma by network analysis. Oncogene. 2016;35(5):608-20. PMCID: 4641815.
Bhargava V, Ko P, Willems E, Mercola M, Subramaniam S. Quantitative transcriptomics using designed primer-based amplification. Sci Rep. 2013;3:1740. PMCID: 3638165.
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