BBS Faculty Member - Frederick Alt

Frederick Alt

Department of Genetics

Boston Children's Hospital
Karp Family Research Building, Rm. 09216
One Blackfan Circle
Boston, MA 02115
Tel: 617-919-2539
Fax: 617-730-0948
Email: alt@enders.tch.harvard.edu
Lab Members: 8 postdoctoral fellows, 5 graduate students, 4 instructors/Lecuturers

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 continue to employ biochemical, molecular and mouse modeling approaches to elucidate mechanisms by which the RAG endonuclease and Activation Induced Cytidine Deaminase function on DNA to initiate, respectively, VDJ recombination and CSR. One focus of this work is to elucidate how the DNA lesion generating activities of these lymphocyte-specific enzymes is directed to specific antigen receptor locus substrates and not to off targets that could generate chromosomal translocations and deletions that contribute to lymphoid cancers. 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, the lab developed a high throughput genomic translocation sequencing (HTGTS) to identify the translocations genome wide that arise from fixed DSBs. This approach also identifies sites of endogenous genomic DSBs including RAG or AID off-target sequences and transcription start sites. Ongoing work seeks to elucidate 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 cancer cells.

Last Update: 7/10/2014

Publications

For a complete listing of publications click here.

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

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.

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

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

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.