What is known about the role of germline histone H3.3 mutations in development?
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Germline mutations in histone H3.3, specifically in the genes H3F3A and H3F3B, have been identified as having significant roles in development, with implications for both neurologic dysfunction and congenital anomalies, without directly leading to malignancies. These mutations disrupt interactions with DNA, other histones, and histone chaperone proteins, leading to aberrant post-translational modification (PTM) patterns and upregulated gene expression related to mitosis and cell division, thereby suggesting a mechanism distinct from cancer-associated somatic histone mutations but converging on the control of cell proliferation. Research has shown that these germline mutations result in a greater proliferative capacity in patient cells, indicating a fundamental role in regulating cellular growth and division. This is further supported by findings in model organisms, where systematic mutation of histone H3 genes, including H3.3, has helped delineate the functional roles of histone residues in development and disease. Moreover, the replication-independent nature of H3.3 and its involvement in maintaining genome integrity under stress conditions highlight its critical role in development and stress response. The specific mutation H3.3K27M, while a hallmark of certain pediatric gliomas, also affects chromatin structure and function, leading to increased accessibility at key regulatory regions for genes involved in neurogenesis and NOTCH signaling pathways. This suggests that H3.3 mutations can influence developmental pathways by altering the epigenetic landscape. Additionally, the impact of H3.3 mutations extends to chromosomal defects and developmental abnormalities in model organisms, further underscoring the variant's importance in developmental processes. In summary, germline mutations in histone H3.3 play a pivotal role in development by affecting gene expression, chromatin structure, and cellular proliferation, with significant implications for neurodevelopment and congenital anomalies, distinct from their role in oncogenesis.
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2 Citations | Histone H3.3 gene targeting (H3f3a) in mice led to developmental lethality, indicating essential roles in development. Specific impacts on gene expression and histone modifications were observed. |
| Loss of histone H3.3 in C. elegans leads to DNA replication defects, altered origin dynamics, replication checkpoint activation, delayed cell cycle, and increased lethality, impacting development under stress conditions. | |
01 Mar 2019 1 Citations | Germline histone H3.3 mutations cause a severe neurodegenerative disorder with unique functional effects, distinct from somatic mutations, impacting cell proliferation and human development. |
| Histone H3.3 K27M mutation in DIPG affects chromatin structure, implicating neurodevelopmental factors like ASCL1 and NEUROD1, leading to increased oncogenic gene expression reversible upon mutation correction. | |
| Histone H3.3 K27M mutation in DIPG affects chromatin structure, implicating neurodevelopmental factors like ASCL1 and NEUROD1, leading to increased oncogenic gene expression reversible upon mutation correction. | |
| Germline histone H3.3 mutations, like H3.3 K27M, disrupt H3.3 Ser31 phosphorylation, leading to chromosome missegregation and gliomagenesis, impacting development and tumor formation. | |
| Mutations in germline histone H3.3, specifically at the 31st amino acid, disrupt histone inheritance, leading to abnormal germ cell populations and altered genomic occupancy, impacting development in Drosophila. | |
| Germline mutations in histone H3.3 (H3F3A and H3F3B) cause a neurodegenerative disorder with developmental delay, neurologic dysfunction, and congenital anomalies, impacting cell proliferation and chromatin regulation. | |
11 Citations | Germline histone H3.3 mutations play a crucial role in defining chromatin function in mammalian development, contributing to changes in the epigenetic landscape and cancer development. |
1 Citations | Distinct N-terminal amino acid mutations in germline histone H3.3 impact stem cell lineage by altering genomic occupancy and function, influencing cell fate determination and differentiation in Drosophila male germline. |
Related Questions
Does the G34W mutation of histone H3.3 lead to segregation defects?4 answersThe G34W mutation of histone H3.3 does not directly lead to segregation defects. However, mutations like G34R/V in H3.3 have been shown to induce chromosomal instability (CIN) in pediatric high-grade gliomas (pHGG) by affecting phosphorylation at S31 and reducing H3K36 trimethylation. This CIN induced by G34 mutations contributes to tumorigenesis, as evidenced by reduced survival and increased tumor formation in mice overexpressing H3.3 G34R or S31A mutants. On the other hand, the G34W mutation in giant cell tumors of bone (GCT) alters the epigenome, transcriptome, and secreted proteome, promoting neoplastic growth and bone destruction without directly causing segregation defects.
What is known about the G34W mutation of histone H3 in adipocytes??10 answersThe G34W mutation of histone H3, specifically in the context of adipocytes, is not directly discussed in the provided contexts. However, insights into the mutation's broader effects on cellular behavior, gene expression, and tumorigenesis can be inferred from studies on other cell types, particularly in relation to bone tumors and gliomas, which may offer indirect clues about its potential impact on adipocytes.
The G34W mutation in histone H3.3 has been identified as a characteristic mutation in Giant Cell Tumor of Bone (GCTB) and is associated with altered cellular growth behavior, gene expression, and chromatin compaction in affected cells. This mutation directly alters the enhancer chromatin landscape by impeding methylation at lysine 36 on histone H3 (H3K36), promoting an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers. Such modifications could potentially influence adipocyte differentiation or function, given the importance of chromatin landscape in cell differentiation processes.
Moreover, the G34W mutation has been shown to be expressed in the nuclei of mononuclear stromal cells but not in osteoclast-like giant cells within GCTB, suggesting a cell-type-specific expression pattern that could similarly affect adipocytes, which are derived from mesenchymal stem cells. The mutation's role in promoting increased proliferation, colony formation, and infiltration in primary cell lines from GCTB patientsindicates a potential for altered adipocyte behavior, although this has not been explicitly studied.
Additionally, the mutation has been implicated in driving tumorigenesis through mechanisms such as compromised DNA damage repair and increased genomic instability, as well as through effects on global methylation levels and specific gene hypermethylation. While these studies do not directly address adipocytes, they highlight the profound impact of the G34W mutation on cellular function and genomic integrity, suggesting possible implications for adipocyte biology that warrant further investigation.
In summary, while the direct effects of the G34W mutation of histone H3 on adipocytes are not detailed in the provided contexts, the mutation's known impact on cellular growth, gene expression, and chromatin architecture in other cell types suggests potential areas of interest for future research into its role in adipocyte function and disease.
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