Background
Dr. Mollie Meffert is an associate professor of biological chemistry and neuroscience at the Johns Hopkins University School of Medicine. Her research focuses on the regulation of neuronal gene expression in health and disease. Dr. Meffert currently serves as the Vice Director of the Department of Biological Chemistry.
Research Description
The Meffert lab investigates mechanisms underlying enduring change in mammalian nervous system function in health and disease. We are interested in how cells in the nervous system make decisions to turn genes on or off, and how those decisions are remembered in processes such as development or plasticity, and in injury or disease. The goal of the Meffert lab is to gain a mechanistic understanding of how selective gene programs are recruited and maintained to alter synaptic, neuronal, and cognitive function. Rather than focusing on single genes, we investigate the upstream processes that allow coordinate regulation of many genes to achieve biological impact. Cell-specific and subcellularly localized posttranscriptional control by RNA-binding proteins and noncoding RNAs is an ongoing focus.
Our laboratory elucidated a post-transcriptional mechanism capable of organizing pro-growth gene programs in which activity-dependent regulation of microRNA (miRNA) production governs the selection of gene targets for protein synthesis. An RNA-binding protein, Lin28, is one activity-responsive factor that promotes pro-growth protein synthesis by downregulating only select miRNAs (e.g. the family of let-7 ‘growth-suppressor’ miRNAs), which repress pro-growth genes. In neurons, pro-growth mRNA targets of the let-7 miRNAs include mRNA for proteins involved in excitatory synaptic function, as well as growth, metabolism, and repair. In recent work, we develop discovery-based sequencing strategies to reveal in vivo small RNA targets through the production of small RNA:target chimeric molecules.
Dr. Meffert’s work has been recognized with awards including the: March of Dimes research scholar, Simons Foundation Autism Research Initiative award, PLU Rho Award, Alfred P. Sloan Research Fellow Award, Hamilton Smith Award for Innovative Science, and The Sontag Foundation Distinguished Scientist and Distinguished Alumni Awards.
Dr. Meffert and her laboratory are the current recipients of the Eric C. Aker Award Endowment through the Braude Foundation.
Expertise
Dr. Meffert received her undergraduate degree (BS) from Stanford University. She earned her MD/PhD in neuroscience from Stanford University School of Medicine and completed a postdoctoral fellowship at California Institute of Technology with Dr. David Baltimore.
Areas of research expertise in Dr. Meffert’s laboratory include molecular neuroscience, RNA biology, and gene expression. Her laboratory uses tools of molecular diagnostics, biochemistry, computational biology, quantitative imaging, and mouse and human genetic models of disease
Lab Members
Xinbei Li (BC graduate student), Bonita Powell (BCMB graduate student), Emily Eiss (BCMB graduate student), Ariella Kornfeld (BCMB graduate student), Sydney Pettit (BCMB graduate student), Preksha Jerajani (research technician), Anselmo Rivera (Hopkins undergraduate)
Selected Publications
- Xinbei Li, William T. Mills IV, Daniel S. Jin, and Mollie K.Meffert. (2024), Genome-wide and cell-type-selective profiling of in vivo small noncoding RNA:target RNA interactions by chimeric RNA sequencing. Cell Reports Methods, 4, 100836.
- Megha Subramanian, William T. Mills IV, Manish D Paranjpe, Uche Onuchukwu, Manasi Inamdar, Amanda R. Maytin, Xinbei Li, Joel L. Pomerantz, and Mollie K.Meffert. (2023), Growth suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency. iScience, 27 (1) 108676.
- William T. Mills IV, Sreenivas Eadara, Andrew E. Jaffe, and Mollie K. Meffert. (2022), SCRAP: a bioinformatic pipeline for the analysis of small chimeric RNA-seq data. RNA 29 (1); 1-17.
- Alexandra M Amen, Claudia R. Ruiz, Jay Shi, Megha Subramanian, Daniel Pham, and Mollie K. Meffert, (2017) A rapid induction mechanism for Lin28a in trophic responses. Molecular Cell, 65 (3); 490 – 503.
- Erica C. Dresselhaus, Matthew C. Boersma, and Mollie K. Meffert, (2018), Targeting of NF-kB to dendritic spines is required for synaptic signaling and spine development. J.Neurosci., 8(17); 4093-4103. PMID 29555853.
- Laurel M. Oldach, Kirill Gorshkov,William T. Mills, Jin Zhang*, and Mollie Meffert* (2018), A biosensor for MAPK-dependent Lin28 signaling. Molecular Biology of the Cell, 29(10), 1157-1167. PMID29540527.
- Yu-Wen A. Huang*, Claudia R. Ruiz*, E.C.H. Eyler*, Kathie Lin, and Mollie K. Meffert. “Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis.” Cell, 148(5); 933-946. 2012.
Description of Research
Animals are intimately associated with communities of microorganisms collectively referred to as the microbiota. The bacteria, archaea, fungi, and viruses that make up the animal microbiota profoundly shape the physiology of their host, altering host metabolism, immune function, and development. This powerfully positions the microbiota as a tool that we can use to influence host biology in meaningful ways.
However, the microbiota is incredibly complex, making it difficult to properly describe, let alone to intentionally manipulate. This is especially true with the gastrointestinal/gut microbiota, where hundreds of poorly characterized microbial species that vary across hosts collectively shape host physiology at multiple levels. Still, the foundations of these complex relationships are shared across different hosts and different contexts, so it is often possible to generalize specific mechanisms across unique microbiotas.
The lab of Host-Microbe Dynamics works to define the fundamental principles of symbiotic relationships between animals and their microbiota. We focus on how the microbiota senses, responds to, and interacts with host lipid metabolism, neurotransmitters, and physical parameters. Ultimately, our goal is to better define the host-microbe relationship and to understand how we can exploit the microbiota to improve host health.
Lab Members
- Grace Heiting, research technologist, Department of Biological Chemistry
- Tanae Lewis, graduate student, GPBC
- Kamal Kaur, undergraduate student
- Sarah Rosental, undergraduate student
Publications
§=corresponding, *=these authors contributed equally
- Jonathan B. Lynch§, Gonzalez EL, Choy K, Faull KF, Jewell T, Arrellano A, Liang J, Yu KB, Paramo J, Hsiao EY. Gut microbiota Turicibacter strains differentially modify bile acids and host lipids. Nature Communications 14(3669), 2023. bioRxiv https://www.biorxiv.org/content/10.1101/2022.06.27.497673v2.
- Jonathan B. Lynch§, Hsiao EY. Toward understanding links between the microbiome and neurotransmitters. Annals of the New York Academy of Sciences 1-7, 2023. -Highlighted in H1 Connect, 2023.
- Jonathan B. Lynch§, James NG, McFall-Ngai M, Ruby EG, Shin S, Takagi D. Transitioning to confined spaces impacts bacterial swimming and escape response. Biophysical Journal 121(13), 2022. bioRxiv https://www.biorxiv.org/content/10.1101/2021.09.15.460467v1.
- Jonathan B. Lynch, Bennett BD, Merrill BD, Ruby EG, Hryckowian AJ. A model symbiosis reveals host- and symbiont-derived phage protection mechanisms. Cell Reports 38(7), 2022. bioRxiv https://www.biorxiv.org/content/10.1101/2021.07.09.451802v1.
- Vroom M, Rodruiguez-Ocasio Y, Jonathan B. Lynch, Ruby E, Foster J. Modeled microgravity alters lipopolysaccharide and outer membrane vesicle production of the beneficial symbiont Vibrio fischeri. npj Microgravity 7(8), 2021.
- Cohen SK, Aschtgen M‐S, Jonathan B. Lynch, Koehler S, Chen F, Escrig S, Daraspe J, Ruby EG, Meibom A, McFall-Ngai M. Tracking the cargo of extracellular symbionts into host tissues with correlated electron microscopy and nanoscale secondary ion mass spectrometry imaging. Cellular Microbiology 22, 2020.
- Jonathan B. Lynch§, Hsiao EY. Microbiomes as sources of emergent host phenotypes. Science, (365)6460, 2019. –Highlighted in Faculty Opinions, 2020
- Schwartzman JA*, Jonathan B. Lynch*, Flores Ramos S, Zhou L, Apicella MA, Yew JY, Ruby EG. Acidic pH promotes lipopolysaccharide modification and alters colonization in a bacteria–animal mutualism. Molecular Microbiology, 112(4), 2019.
- Jonathan B. Lynch, Schwartzman JA, Bennett BD, McAnulty SJ, Knop M, Nyholm SV, Ruby EG. Ambient pH Alters the Protein Content of Outer Membrane Vesicles, Driving Host Development in a Beneficial Symbiosis. Journal of Bacteriology, 201(20), 2019.
- Jonathan B. Lynch§ and Alegado RA§. Spheres of hope, packets of doom: the good and bad of Outer Membrane Vesicles (OMVs) in interspecies and ecological dynamics. Journal of Bacteriology, 199(15), 2017.
- Aschtgen MS, Jonathan B. Lynch, Koch E, Schwartzman J, McFall-Ngai M, Ruby E. Rotation of Vibrio fischeri flagella produces outer membrane vesicles that induce host development. Journal of Bacteriology 198(16), 2016.
- Ng KM, Ferreyra JA, Higginbottom SK, Jonathan B. Lynch, Kashyap PC, Gopinath S, Naidu N, Choudhury B, Weimer BC, Monack DM, Sonnenburg JL. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502(7469), 2013.
- Jonathan B. Lynch and Sonnenburg JL. Prioritization of a plant polysaccharide over a mucus carbohydrate is enforced by a Bacteroides hybrid two-component system. Molecular Microbiology 85(3), 2012.
- Harrison JE, Jonathan B. Lynch, Sierra LJ, Blackburn LA, Ray N, Collman RG, Doms RW. Baseline resistance of primary human immunodeficiency virus type 1 strains to the CXCR4 inhibitor AMD3100. Journal of Virology 82(23), 2008.