The Role of TET Proteins in the Epigenetic Regulation of Neural Gene Expression and Behavior

Understanding how genes affect behavior is critical to develop precise therapies for human behavioral disorders. The ability to investigate the relationship between genes and behavior has been greatly advanced over the last few decades due to progress in gene-targeting technology. Recently, the Tet gene family was discovered and implicated in epigenetic modification of DNA methylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). 5hmC and its catalysts, the TET proteins, are highly abundant in the postnatal brain but with unclear functions. To investigate their neural functions, we generated new lines of Tet1 and Tet3 mutant mice using a gene targeting approach. We designed both mutations to cause a frameshift by deleting the largest coding exon of Tet1 (Tet1Δe4) and the catalytic domain of Tet3 (Tet3Δe7-9). As Tet1 is also highly expressed in embryonic stem cells (ESCs), we generated Tet1 homozygous deleted ESCs through sequential targeting to compare the function of Tet1 in the brain to its role in ESCs. To test our hypothesis that TET proteins epigenetically regulate transcription of key neural genes important for normal brain function, we examined transcriptional and epigenetic differences in the Tet1Δe4 mouse brain. The oxytocin receptor (OXTR), a neural gene implicated in social behaviors, is suggested to be epigenetically regulated by an unknown mechanism. Interestingly, several human studies have found associations between OXTR DNA hypermethylation and a wide spectrum of behavioral traits and neuropsychiatric disorders including autism spectrum disorders. Here we report the first evidence for an epigenetic mechanism of Oxtr transcription as expression of Oxtr is reduced in the brains of Tet1Δe4-/- mice. Likewise, the CpG island overlapping the promoter of Oxtr is hypermethylated during early embryonic development and persists into adulthood. We also discovered altered histone modifications at the hypermethylated regions, indicating the loss of TET1 has broad effects on the chromatin structure at Oxtr. Unexpectedly, we discovered an array of novel mRNA isoforms of Oxtr that are selectively reduced in Tet1Δe4-/- mice. Additionally, Tet1Δe4-/- mice display increased agonistic behaviors and impaired maternal care and short-term memory. Our findings support a novel role for TET1 in regulating Oxtr expression by preventing DNA hypermethylation and implicate TET1 in social behaviors, offering novel insight into Oxtr epigenetic regulation and its role in neuropsychiatric disorders.

Micro-Fabricated Surface Trap and Cavity Integration for Trapped Ion Quantum Computing

Atomic ions trapped in micro-fabricated surface traps can be utilized as a physical platform with which to build a quantum computer. They possess many of the desirable qualities of such a device, including high fidelity state preparation and readout, universal logic gates, long coherence times, and can be readily entangled with each other through photonic interconnects. The use of optical cavities integrated with trapped ion qubits as a photonic interface presents the possibility for order of magnitude improvements in performance in several key areas of their use in quantum computation. The first part of this thesis describes the design and fabrication of a novel surface trap for integration with an optical cavity. The trap is custom made on a highly reflective mirror surface and includes the capability of moving the ion trap location along all three trap axes with nanometer scale precision. The second part of this thesis demonstrates the suitability of small micro-cavities formed from laser ablated fused silica substrates with radii of curvature in the 300-500 micron range for use with the mirror trap as part of an integrated ion trap cavity system. Quantum computing applications for such a system include dramatic improvements in the photonic entanglement rate up to 10 kHz, the qubit measurement time down to 1 microsecond, and the measurement error rates down to the 10e-5 range. The final part of this thesis details a performance simulator for exploring the physical resource requirements and performance demands to scale such a quantum computer to sizes capable of performing quantum algorithms beyond the limits of classical computation.