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Divergent expression patterns and regulation of the H3.3-encoding genes during normal development and carcinogenesis

ABSTRACT: Minor histone variants replace canonical histones in replication-independent manner, altering chromatin structure and thereby affecting gene expression. This constitutes a distinct mechanism of genome regulation, extending the function of nucleosomes beyond ‘simple’ DNA packaging. In an unusual genomic arrangement, two unique genes (H3F3A and H3F3B), encode the same protein – a developmentally essential histone H3.3. Mutations in each of these genes occur in different cancers, including pediatric brain tumors. To investigate this phenomenon we performed an integrative analysis of the expression, regulatory sequences, and mutability of these genes. We report that H3F3A and H3F3B have distinct expression patterns in human cell types. This difference is maximal between differentiated and stem-like cells, whose expression profile resembles that of cancers. The transcription factors, including Oct4/Sox2 and N-Myc, can differentially regulate these genes, and we demonstrate that Oct4 and Sox2 upregulate H3f3a but not H3f3b in mouse ESCs. Notably, the increased H3F3A contribution to the total H3.3 pool correlates with tumor malignancy. We infer that a similar increase in the H3F3A ‘transcriptional dosage’ in stem-like cells enables the mutations in this gene to impact cell fate determination. Collectively, our findings provide new insights into the interplay between gene expression and DNA mutations in chromatin-associated factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE89326 | GEO | 2020/10/29

REPOSITORIES: GEO

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