Characterizing the Essential Roles of Histone Acetyl Transferase 1 during Epigenetic Inheritance in a Mammalian Model
Year: 2015
Type: dissertation
Abstract: Hat1 is a histone acetyltransferase responsible for an evolutionarily conserved diacetylation of newly synthesized histone H4 at lysines 5 and 12 and is required for the proper acetylation of newly synthesized histone H3 at lysines 9 and 27. Hat1 is essential for viability in mice. Complete deletion of murine Hat1 (Hat1-/-) is neonatal lethal, resulting in developmental defects in the embryonic lung. Hat1 has long been believed to play a role in epigenetic inheritance, however evidence to support this hypothesis has remained elusive and a role for this pattern of histone acetylation during mammalian development has been largely uncharacterized. By analyzing the chromatin architecture of Hat1-/- mouse embryonic fibroblasts, we discovered 853 loci-specific peaks of H4K5 acetylation dependent upon the presence of Hat1 that are also necessary for proper gene activation. Consistent with this observation, an in vivo transcriptome study of E17.5 Hat1-/- embryonic lungs demonstrated 172 RNA transcripts found to be under-expressed at least 2-fold or greater when compared to the wild-type. Furthermore, the down-regulation of Sftpa1 and Cyp-2f2 suggests that the developmental defects observed in the lungs of Hat1-/- mice may be indicative of defects in the cellular differentiation of alveolar and Clara cell precursors. Additionally, mice containing a liver-specific knockout of Hat1 demonstrate a high incidence of rare liver cancer types, such as hepatoblastoma and hepatocholangiocellular carcinoma, that are known to arise from early hepatocyte precursors. Together, our findings suggest a role for Hat1 as an epigenetic regulator involved in the appropriate activation of gene required for cellular differentiation from stem cell-like cellular precursors.
Author: Harrison Kaufman
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2206832815