Hannah Kempton

All Publications

• Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits CELL REPORTS Platt, R. J., Zhou, Y., Slaymaker, I. M., Shetty, A. S., Weisbach, N. R., Kim, J., Sharma, J., Desai, M., Sood, S., Kempton, H. R., Crabtree, G. R., Feng, G., Zhang, F. 2017; 19 (2): 335-350

  Abstract

  Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We generated germline mutant mice with loss-of-function mutations in Chd8, a de novo mutation strongly associated with ASD, and demonstrate that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8(+/-) mice display a broad, brain-region-specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell-cycle regulation. We also find altered synaptic physiology in medium spiny neurons of the nucleus accumbens. Perturbation of Chd8 in adult mice recapitulates improved acquired motor learning behavior found in Chd8(+/-) animals, suggesting a role for CHD8 in adult striatal circuits. These results support a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.

  View details for DOI 10.1016/j.celrep.2017.03.052

  View details for PubMedID 28402856

• CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling CELL Platt, R. J., Chen, S., Zhou, Y., Yim, M. J., Swiech, L., Kempton, H. R., Dahlman, J. E., Parnas, O., Eisenhaure, T. M., Jovanovic, M., Graham, D. B., Jhunjhunwala, S., Heidenreich, M., Xavier, R. J., Langer, R., Anderson, D. G., Hacohen, N., Regev, A., Feng, G., Sharp, P. A., Zhang, F. 2014; 159 (2): 440-455

  Abstract

  CRISPR-Cas9 is a versatile genome editing technology for studying the functions of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse. We demonstrated in vivo as well as ex vivo genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells. Using these mice, we simultaneously modeled the dynamics of KRAS, p53, and LKB1, the top three significantly mutated genes in lung adenocarcinoma. Delivery of a single AAV vector in the lung generated loss-of-function mutations in p53 and Lkb1, as well as homology-directed repair-mediated Kras(G12D) mutations, leading to macroscopic tumors of adenocarcinoma pathology. Together, these results suggest that Cas9 mice empower a wide range of biological and disease modeling applications.

  View details for DOI 10.1016/j.cell.2014.09.014

  View details for Web of Science ID 000343095600023

  View details for PubMedID 25263330

  View details for PubMedCentralID PMC4265475