Heads of Laboratories
C. David Allis, Ph.D.
Joy and Jack Fishman Professor
Laboratory of Chromatin Biology and Epigenetics
Chromatin is the physiological template of the human genome. The histone proteins within chromatin, their posttranslational modifications, and the enzyme systems responsible for generating them are highly conserved through evolution. Meanwhile, elaborate mechanisms have evolved to introduce meaningful variation into chromatin to alter gene expression and other important biological processes.
More recently, researchers in the Allis lab proposed that the mammalian genome is indexed by H3 variants so as to control whether genes are constitutively expressed or remain silent. The Allis lab produced the first genome-wide maps of H3.3 localization, first in mammalian embryonic stem cells and then again after the cells had differentiated to become neurons. Biochemical approaches have led to chaperone complexes that engage H3.3 selectively, depositing it into distinct regions of the genome. One of these chaperone systems is mutated in a significant fraction of patients who suffer from pancreatic neuroendocrine tumors, and H3.3 mutations are also highly specific to pediatric gliomas. Dr. Allis and his colleagues hypothesize these mutations can alter the recruitment and activity of histone modifying complexes and therefore alter the epigenetic landscape and dysregulate gene expression. Given the restricted distribution of H3.3 mutations to pediatric gliomas, they further hypothesize that cell lineage–specific cellular context is crucial for the ability of these mutations to mediate oncogenesis. Active investigations are under way to test these hypotheses with collaborators in more clinically relevant settings, including human patients.
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