PiN Faculty Member - Frederick Alt, PhD

Frederick Alt, PhD

Boston Children's Hospital
Karp Family Research Building, Rm. 09216
1 Blackfan Circle
Boston, MA 02115
Tel: 617-919-2539
Fax: 617-730-0948
Email: alt@enders.tch.harvard.edu



The broad focus of our lab is the elucidation of mechanisms that generate antigen receptor diversity in the Immune system and mechanisms that maintain genomic stability in mammalian cells. Over the past decade we have developed remarkably sensitive high throughput approaches to elucidate translocations and DNA breaks genome-wide at nucleotide resolution and move studies of chromosomal translocations, deletions, and amplifications into the post-genomics era. More recently, we have further advanced these methods to develop powerful V(D)J recombination and IgH class switch recombination assays that have led to us to generate a much more in depth understanding of the mechanistic aspects of these processes in B lymphocyte lineage cells and the role of topological chromatin domains and chromosomal loop domains in influencing DSB generation and joining during these processes. Our studies have also revealed many new insights into mechanisms by which off-target activities associated with the antigen receptor locus gene rearrangement processes in B and T lineage cells lead to oncogenic genomic rearrangements and lymphoid cancers. We have further exploited our discoveries in these general areas to generate powerful new mouse models to test vaccination strategies for generating human HIV-1 broadly neutralizing antibodies and for optimizing or discovering human therapeutic antibodies more generally. We also have further advanced our high throughput V(D)J recombination assays to develop a highly sensitive antibody somatic hypermutation/affinity maturation assay (“Landmarc"-Seq) that has allowed us to directly address the enigmatic nature of chronic gut Peyer’s Patch (PP) antibody repertoires in mice and we are now extending these studies to humans. Finally, as a complementary goal to our immunology studies, we have extended our research focus to employ our powerful new approaches to discover genes that recurrently break in neuronal stem and progenitor cells, potentially providing new insights into potential mechanisms of cellular diversity in the brain and mechanistic factors that could contribute various neuropsychiatric diseases and brain cancer.



Last Update: 6/25/2018



Publications

Yeap, L.S., Hwang, J.K., Du, Z., Meyers, R.M., Meng, F-L., Jakubauskaite, A., Liu, M., Mani, V., Neuberg, D., Kepler, T.B., Wang, J.H. and Alt, F.W. (2015) Sequence-intrinsic mechanisms that target AID mutational outcomes on antibody genes, Cell, 163, 1124-1137. PMC4751889

Hu, J., Zhang, Y., Zhao, L., Frock, R.L., Du, Z., Meyers, R.M., Meng, F-L., Schatz, D.G. and Alt, F.W. (2015) Chromosomal loop domains direct the recombination of antigen receptor genes.
Cell, 163, 947-959. PMC4660266  

Dong, J.,
Panchakshari, R.A., Zhang, T., Zhang, Y., Hu, J., Volpi, S.A.. Meyers, R.M., Ho, Y-J., Du, Z., Robbiani, D.F., Meng F., Gostissa, M., Nussenzweig, M.C., Manis, J.P. and Alt, F.W. (2015) Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching. Nature, 525, 134-139. PMC4592165

Wei, P-C., Chang, A.N., Kao, J., Du, Z., Meyers, R.M., Alt, F.W. and Schwer, B. (2016) Long neural genes harbor recurrent DNA break clusters in neural stem/progenitor cells.
Cell, 164, 644-655. PMC4752721

Tian, M., Cheng, C., Chen, X., Duan, H., Cheng, H-L., Dao, M., Sheng, Z., Kimble, M., Wang, L., Lin, S., Schmidt, S.D., Du, Z., Joyce, G., Chen, Y., DeKosky, B.J., Chen, Y., Normandin, E., Cantor, E., Chen, R., Doria-Rose, N.A., Zhang, Y., Shi, W., Kong, W-P., Choe, M., Georgiev, I.S., Huang, H-Y., Jain, S., McGuire, A.T., Georgeson, E., Menis, S., Schief, W.R., Stamatatos, L., Kwong, P.D., Shapiro, L., Haynes, B.F., Mascola, J.R. and Alt, F.W. (2016) Induction of HIV neutralizing antibody lineages in mice with diverse precursor repertories.
Cell. 166, 1471–1484. PMC5103708

Hwang, J.K., Wang, C., Du, Z., Meyers, R.M., Kepler, T.B., Neuberg, D., Kwong, P.D., Mascola, J.R., Joyce, M.G., Bonsignori, M., Haynes, B.F., Yeap, L-S. and Alt, F.W. (2017) Sequence intrinsic somatic mutation mechanisms contribute to affinity maturation of VRC01-class HIV-1 broadly neutralizing antibodies. Proc. Natl. Acad. Sci. USA. 114, 8614-8619. PMC5559054.

Panchakshari, R.A., Zhang, X., Kumar, V, Du, Z., Wei, P.C., Kao, J., Dong, J. and Alt, F.W. (2018) DNA double-strand break response factors influence end-joining features of IgH class switch and general translocation junctions. Proc. Natl. Acad. Sci. U S A. 115, 762-767. PMC5789958

Jain, S., Ba, Z., Zhang, Y., Dai, H-Q and Alt, F.W. CTCF-binding elements mediate accessibility of RAG substrates during chromatin scanning.
Cell May 18. pii: S0092-8674(18)30566-X. doi: 10.1016/j.cell.2018.04.035. [Epub ahead of print]




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