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 processes. 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 high throughput genomic translocation sequencing strategies to identify the translocations genome wide that can arise from fixed DSBs. This approach also identifies sites of endogenous 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.
About Fred Alt
Dr. Alt received his Ph.D. in Biology from Stanford University in 1977 with Robert Schimke and he did his postdoctoral work at MIT with David Baltimore. He was a Professor at Columbia University from 1982-1991, where he became an HHMI Investigator in 1987. In 1991, Dr. Alt moved to Harvard Medical School as a Professor of Genetics and Pediatrics, an HHMI Investigator at Boston Children's Hospital and a Senior Investigator at the Immune Disease Institute. He was appointed Charles A. Janeway Professor of Pediatrics in 1993 and Scientific Director of the Immune Disease Institute in 2005. He became Director of the Immune Disease Institute and Program in Cellular and Molecular Medicine of Children's Hospital in 2009 and President of the Immune Disease Institute in 2010. Dr. Alt has been elected to the U.S. National Academy of Sciences, the American Academy of Arts and Sciences, the American Academy of Microbiology, and the European Molecular Biology Organization. He has received the Clowes Memorial Award from the American Association of Cancer Research; the Rabbi Shai Shacknai Prize from The Hebrew University, the Pasarow Foundation Prize for Extraordinary Achievement in Cancer Research, the Leukemia & Lymphoma Society de Villiers International Achievement Award, the Irvington Institute Immunology Award, the National Cancer Institute Alfred K. Knudson Award for pioneering contributions that have revolutionized the field of Cancer Genetics, the American Association of Immunologists AAI-Huang Meritorious Career Award, the William B. Coley Award from the Cancer Research Institute, and the Novartis Basic Immunology Prize for his discoveries on B cell development and antigen responses.
Dr. Alt has mentored over 100 students and research fellows, many of whom have become leaders in immunology, genetics, or cancer biology and has received the American Association of Immunologists Excellence in Mentoring Award. The Cancer Research Institute (New York) annually presents the Frederick W. Alt Award for New Discoveries in Immunology.