Integrated Calendar

This work deals with extinction of isolated populations caused by intrinsic noise of birth-death processes. We model the dynamics of a population in a "refuge" as a Markov process which involves births and deaths on discrete lattice sites and random migrations between neighboring sites. In the first class of models the zero population size is an unstable fixed point of the deterministic on-site dynamics. In the second class it is a stable fixed point, corresponding to what is known in ecology as Allee effect. Assuming
a large population size, we develop WKB approximation to the master equation. The resulting effective classical mechanics encodes the most probable path of the population toward extinction and the mean time to extinction. In the fast-migration limit this description is closely related to the one suggested by Elgart and Kamenev (2004). We classify possible regimes of population extinction with and without Allee effect and for different types of refuge, and solve several examples. For a very strong Allee effect
the extinction problem can be mapped into the over-damped limit of theory of homogeneous nucleation due to Langer (1969). In this regime we predict an optimal refuge size that makes the population least prone to extinction.

Normal development and disease depend strongly on epigenetic regulation of gene expression. Polycomb group (PcG) proteins dynamically define cellular identities through the epigenetic repression of key developmental genes via chromatin-modifying activities. PcG proteins form large multimeric complexes that are recruited to DNA regulatory elements termed polycomb response elements (PREs) via their interaction with sequence specific DNA binding proteins. These proteins recognize specific DNA motifs clustered at PREs, however, paradoxically our genome wide mapping studies revealed that they are also bound to active chromatin sites that are devoid of PcG proteins. Thus, an exhaustive definition of PREs is lacking and it is not understood how PREs specifically recruit PcG complexes. In addition the intriguing possibility that different subclasses of PREs exist that differ in their way to recruit PcG complexes remains unconfirmed. These long standing questions are of highest importance, since deregulation of PcG proteins and their recruiting factors result in aberrant expression of PcG-target genes leading to cell over proliferation and tumorigenesis. To crack the code of PcG recruitment we are currently mapping PREs and PcG-recruiting factors across different Drosophila species. We are analyzing how PRE sequences behave during evolution to identify the complete set of sequence and protein requirements for PcG recruitment.

Histone monoubiquitylation is implicated in critical regulatory processes. We explored the roles of histone H2B ubiquitylation in human cells by reducing the expression of hBRE1/RNF20, the major H2B-specific E3 ubiquitin ligase. While H2B ubiquitylation is broadly associated with transcribed genes, only a subset of genes was transcriptionally affected by RNF20 depletion and abrogation of H2B ubiquitylation. Gene expression dependent on RNF20 includes histones H2A and H2B and the p53 tumor suppressor. In contrast, RNF20 suppresses the expression of several proto-oncogenes, which reside preferentially in closed chromatin and are poorly transcribed despite bearing marks usually associated with active transcription. Remarkably, RNF20 depletion augmented the transcriptional effects of epidermal growth factor (EGF), induced EGF-dependent cell migration, and elicited neoplastic cell transformation. RNF20 may thus be a putative tumor suppressor, acting through selective regulation of a distinct subset of genes.
Our findings implicate the elongation factor TFIIS in the mechanism of RNF20-mediated gene repression. RNF20 is shown to repress transcription elongation through inhibition of TFIIS recruitment to chromatin. Depletion of TFIIS abolishes RNF20-mediated suppression of growth-related genes, and attenuates the cellular response to EGF. Our results strongly suggest that part of the tumor suppressor activities of RNF20 may be mediated via inhibition of TFIIS binding, with consequent downregulation of cancer-promoting genes whose transcriptional elongation relies on TFIIS.

Nanoscale materials enable unique opportunities at the interface between the physical and life sciences, and the interface between nanoelectronic devices and biological systems makes possible communication between these two diverse systems at the length scale relevant to biological function. In this presentation, the development of nanowire nanoelectronic devices and their application as powerful tools for the life sciences will be discussed. First, a brief introduction to nanowire nanoelectronic devices as well as comparisons to other electrophysiological tools will be presented to illuminate the unique strengths and opportunities enabled at the nanoscale. Second, illustration of detection capabilities including signal-to-noise and applications for real-time label-free detection of biochemical markers down to the level of single molecules will be described. Third, the use of nanowire nanoelectronics for building interfaces to cells and tissues will be reviewed. Multiplexed measurements made from nanowire devices fabricated on flexible and transparent substrates recording signal propagation across cultured cells, acute tissue slices and intact organs will be illustrated, including quantitative analysis of the high simultaneous spatial and temporal resolution achieved with these nanodevices. Specific examples of subcellular and near point detection of extracellular potential will be used to illustrate the unique capabilities, such as recording localized potential changes due to neuronal activities simultaneously across many length scales, which provide key information for functional neural circuit studies. Last, emerging opportunities for the creation of powerful new probes based on controlled synthesis and/or bottom-up assembly of nanomaterials will be described with an emphasis on the creation of kinked nanowire probes capable of first intracellular transistor recordings. The prospects for blurring the distinction between nanoelectronic and living systems in the future will be highlighted.