Genetic information is packaged and interpreted by cellular machinery within the context of chromatin, a complex of nucleic acids and regulatory proteins. Histone proteins are major constituents of chromatin. Over a third of patients diagnosed with B-cell lymphomas carry tumor-specific missense mutations in genes encoding one specific subtype of histone proteins, termed linker histone H1. Our recent results show that linker histones act as tumor suppressors in B-cells, wherein H1 loss drives pre-neoplastic expansion during germinal center reaction, and accelerates lymphomagenesis in H1 dose-dependent manner. However, detailed mechanism of how H1 mutations lead to malignancy remains unclear. ...
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Genetic information is packaged and interpreted by cellular machinery within the context of chromatin, a complex of nucleic acids and regulatory proteins. Histone proteins are major constituents of chromatin. Over a third of patients diagnosed with B-cell lymphomas carry tumor-specific missense mutations in genes encoding one specific subtype of histone proteins, termed linker histone H1. Our recent results show that linker histones act as tumor suppressors in B-cells, wherein H1 loss drives pre-neoplastic expansion during germinal center reaction, and accelerates lymphomagenesis in H1 dose-dependent manner. However, detailed mechanism of how H1 mutations lead to malignancy remains unclear. This proposal aims to define the oncogenic mechanism of linker histone mutants in lymphoma, with focus on chromatin mechanisms of malignancy. We hypothesize that (a) individual mutations in H1 found in lymphoma alter chromatin association of mutant proteins, resulting in (b) chromatin decompaction and ectopic redistribution of core histone modifications instructive to aberrant expression of developmentally regulated genes, an effect that (c) may be rescued by stabilizing H1 in chromatin. Together, this work will uncover molecular mechanisms of linker histone mutations in lymphoma, define chromatin effectors of H1 mutant-driven malignancy, and identify new strategies to compensate for H1 deficiency in vivo. Beyond H1 mutant lymphomas, our findings will be immediately relevant to an emerging class of malignancies associated with aberrant chromatin decompaction.
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