Oded Rechavi

C.elegans Parental Experiences Regulate a Critical Decision Made by the Progeny

C. elegans can transmit certain responses transgenerationally, however it is unknown whether these can impact the process of evolution. Here, by studying nematodes that choose whether to self-reproduc...e or outcross, we show that inherited small RNAs affect sexual attraction and mating for multiple generations and thus indirectly control genetic variation. We found that manipulating endogenous small RNA levels in hermaphrodites induces premature secretion of a male-attracting pheromone, increases the prevalence of males, and ultimately elevates the rate of successful mating. Further, stress leads to enhanced sexual attraction which transmits transgenerationally for three generations. Simulations and multigenerational competition experiments demonstrate that the rise in mating, driven by heritable small RNAs that promote sexual attraction, can increase alleles frequencies in the population. This non-DNA based inheritance process could be a mechanism for elevating the rate of outcrossing in challenging environments, when increasing genetic variation is advantageous.

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Siddhesh Kamat

A chemical biology approach towards understanding a human neurological disorder

Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, and Cataract (PHARC) is an autosomal recessive human genetic neurological disorder caused by deleterious (null) mutations to the abhd12 gene... that encodes an integral membrane serine hydrolase enzyme ABHD12, a major and to date, only verified lysophosphatidylserine (lyso-PS) lipase. In this talk, I will discuss our chemical biology approaches towards understanding and mapping the molecular mechanisms that drive the pathology of this disease, and posit new therapeutic paradigms in rectify this early onset neurological disorder.

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Madeline Lancaster

Examining human brain structure and function with cerebral organoids

The human brain exhibits a number of unique characteristics, such as dramatic size expansion and variation in relative abundance of specific neuron populations. In an effort to better understand human... brain development, we developed an in vitro human model system, called cerebral organoids. These 3D tissues are generated from human pluripotent stem cells through directed differentiation and a supportive 3D microenvironment to generate organoids with the stereotypic organization of the early human fetal brain. We have now extended these methods to model later events in neurodevelopment, including neuronal migration and positioning, axon guidance, and neuronal maturation. These newer approaches can model CNS tract formation with the generation of neural circuits, and even functional output through a motor circuit to modulate and activate muscle contractions. Finally, we are continuing to advance these methods and have devised choroid plexus organoids as a model of the human blood-CSF barrier for testing CNS penetrance. These methods are now allowing us to tackle questions previously impossible with more traditional approaches.

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Steven Henikoff

Genome-wide mapping of protein-DNA interaction dynamics

We recently introduced new tools for high-resolution genome-wide chromatin profiling and have applied them to study chromatin organization and dynamics in a variety of model systems, including yeast, ...flies and mammals. Among the questions addressed are: How do transcription factors find their binding sites in DNA packaged into nucleosomes? How are nucleosomes depleted from gene regulatory regions? What is the relationship between nucleosome deposition pathways and chromatin deregulation in disease? Our findings illustrate ways in which chromatin dynamics can play a central role in regulating gene expression and silencing.

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Grant Jensen

Electron cryotomography and the ultrastructure of cells

In the last ten years electron cryotomography (cryo-ET) has made it possible to visualize large macromolecular assemblies inside intact cells in a near-native, "frozen-hydrated" state in 3-D to a few ...nanometers resolution. Increasingly, atomic models of individual proteins and smaller complexes obtained by X-ray crystallography, NMR spectroscopy, or other methods can be fit into cryotomograms to reveal how the various pieces work together inside cells. A few good pictures is therefore sometimes all that is really needed to distinguish between competing models. To illustrate these points, I will present examples of current results from our recent work on bacterial secretion systems and eukaryotic stress responses. The range of cellular samples that cryo-ET can reveal is dramatically expanding with FIB-milling, and will likely soon become dramatically more useful with correlated light and electron microscopy (CLEM) targeting. Two major developments in cryo-ET technology further suggest that cryo-ET will become an important new method for determining the structures of single particles and small proteins as well. First, highly eucentric stages are now allowing tilt-series to be recorded in seconds rather than minutes, opening the possibility of high resolution single particle tomography. Second, cryo-ET of very small crystals ("nanocrystals") offers compelling potential advantages over X-ray crystallography. I will explain these advances and their projected implications with examples from our work.

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