Frederick W. Alt
Boston Children's Hospital
Karp Family Research Building, Rm. 09216
1 Blackfan Circle
Boston, MA 02115
Please see the electronic album of Alt Lab alumni, compiled by HHMI in 2010, titled: "FREDERICK W. ALT: A SUPPORTIVE MENTOR AND HARD-DRIVING SCIENTIST"
The broad focus of the Alt lab is the elucidation of mechanisms that generate antigen receptor diversity in the Immune system and mechanisms that maintain genomic stability in mammalian cells. More specifically, the lab studies V(D)J recombination in developing B and T lymphocytes and IgH heavy chain class switch recombination (CSR) and somatic hypermutation in mature B lymphocytes. Studies of these processes employ biochemical approaches to elucidate molecular mechanisms by which the RAG endonuclease and Activation Induced Cytidine Deaminase function on DNA to initiate, respectively, VDJ recombination and CSR. As one example, our recent studies showed a role for the RNA exosome in targeting AID to both strands of duplex DNA. Other studies focus on the elucidation of genetic and epigenetic chromosomal processes that regulate how RAG and AID are targeted to their specific chromosomal DNA substrates. In this regard, our recent work defined a control region, termed IGCR1, in the IgH locus that regulates proximal versus distal VH usage, lineage-specificity, ordered assembly of VH, D, and JH segments and feedback regulation/allelic exclusion. New studies focus on the use of novel mouse models and various types of high throughput genomic studies to elucidate how AID is targeted during CSR versus SHM in germinal center B cells and to define factors (e.g. sequence motifs, transcription patterns) that generate off-target AID activity during these process. Other studies are aimed at elucidating roles of general DNA double strand break (DSB) repair and response pathways in VDJ recombination and CSR, and the interplay of DSB repair and response pathways in suppressing genomic instability and cancer. A major new lab research area focuses on how organization of the genome in the nucleus influences programmed gene rearrangements and chromosomal translocations. For this purpose, we have developed a high throughput genomic translocation sequencing strategies to identify the translocations genome wide that can arise from fixed DSBs. This approach also identifies sites of endgenous genomic DSBs including RAG or AID off-target sequences and transcription start sites. Our goal is to establish the contribution of mechanistic elements (three dimensional genome organization, DSBs, transcription, epigenetic modifications, repair pathways, etc) that contribute to the formation of translocations and other forms of genomic instability in mouse and human cells.
Publications (Immunology Graduate Students listed in Bold)
1. Chiarle, R., Zhang, Y., Frock, R.L., Lewis, S.M., Molinie, B., Ho, Y-J. Myers, D.R., Choi, V.W., Compagno, M., Malkin, D.J., Neuberg, D., Monti, S., Giallourakis, C.C., Gostissa, M. and Alt, F.W. Genome-wide translocation sequencing reveals mechanisms that shape the translocatome of primary B lymphocytes. Cell. 2011 Sep 30;147(1):107-19
2. Guo, C., Yoon, H.S., Franklin, A, Jain, S., Ebert. A., Cheng, H. L., Hansen, E., Despo, O., Bossen, C., Vettermann, C., Bates, J. G., Richards, N., Myers, D., Patel, H., Gallagher, M., Schlissel, M. S., Murre, C., Busslinger, M., Giallourakis, C. C., and Alt, F. W. CTCF Binding Elements Mediate Control of V(D)J Recombination. Nature. 2011 Sep 11;477(7365):424-30.
3. Zhang, Y., McCord, R.P., Ho, Y-J., Lajoie, B.R., Hildebrand, D.G., Simon, A.C., Becker, M.S., Alt, F.W.# and Dekker, J.# Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell. 2012 Mar 2;148(5):908-21. #Co-corresponding authors
4. Alt, F.W. #, Zhang, Y., Meng, F-L., Guo, C. and Schwer, B. Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell. 2013 Jan 31;152(3): 417-429. #Corresponding Author
5. Wesemann, D.R., Portuguese, A.J., Meyers, R.M. Gallagher, M.P., Cluff-Jones, K., Magee, J.M., Ranchakshari, R.A., Rodig, S.J., Kepler, T.B. and Alt, F.W. Microbal colonization influences early B-lineage development in the gut lamina propria. Nature. 2013 Sep 5;501(7465):112-5. doi: 10.1038/nature12496. Epub 2013 Aug 21.
Last Update: 1/6/2014