Previously we have studies the contribution of histone modifications, DNA methylation and their regulatory enzymes to transcriptional regulation in a variety of cellular systems. Our latest efforts have focused on how histone variants contribute to the regulation of chromatin structure and transcription. Nucleosomes are present throughout the genome and must be dynamically regulated to accommodate binding of transcription factors and RNA polymerase machineries by various mechanisms. Despite the development of protocols and techniques that have enabled us to map nucleosome occupancy genome-wide, the dynamic properties of nucleosomes remain poorly understood, particularly in mammalian cells. The histone variant H3.3 is incorporated into chromatin independently of DNA replication and requires displacement of existing nucleosomes for its deposition. However, it is not clear how deposition of the histone variant is regulated. We developed a system to study the DNA replication-independent turnover of nucleosomes containing the histone variant H3.3 in mammalian cells. By measuring the genome-wide incorporation of H3.3 at different time points following epitope-tagged H3.3 expression, we find three categories of H3.3-nucleosome turnover in vivo: rapid turnover, intermediate turnover and, specifically at telomeres, slow turnover. Our data indicate that H3.3-containing nucleosomes at enhancers and promoters undergo rapid turnover that is associated with active histone modification marks including H3K4me1, H3K4me3, H3K9ac, H3K27ac and the histone variant H2A.Z. The rate of turnover is negatively correlated with H3K27me3 at regulatory regions and with H3K36me3 at gene bodies. In addition, we have worked with our collaborators using model systems including Drosophila flies and chicken to investigate the contribution of chromatin and epigenetic mechanisms to cellular memory and differentiation.
| Baranello, Laura; Kouzine, Fedor; Wojtowicz, Damian et al. (2018) Mapping DNA Breaks by Next-Generation Sequencing. Methods Mol Biol 1672:155-166 |
| Yohe, Marielle E; Gryder, Berkley E; Shern, Jack F et al. (2018) MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma. Sci Transl Med 10: |
| Hodges, H Courtney; Stanton, Benjamin Z; Cermakova, Katerina et al. (2018) Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat Struct Mol Biol 25:61-72 |
| Resto, Melissa; Kim, Bong-Hyun; Fernandez, Alfonso G et al. (2017) O-GlcNAcase is an RNA polymerase II elongation factor coupled to pausing factors SPT5 and TIF1?. J Biol Chem 292:16524-16525 |
| Gryder, Berkley E; Yohe, Marielle E; Chou, Hsien-Chao et al. (2017) PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability. Cancer Discov 7:884-899 |
| Miller, Erik L; Hargreaves, Diana C; Kadoch, Cigall et al. (2017) TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nat Struct Mol Biol 24:344-352 |
| Nakayama, Robert T; Pulice, John L; Valencia, Alfredo M et al. (2017) SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat Genet 49:1613-1623 |
| Stanton, Benjamin Z; Hodges, Courtney; Calarco, Joseph P et al. (2017) Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. Nat Genet 49:282-288 |
| Cooper, James; Ding, Yi; Song, Jiuzhou et al. (2017) Genome-wide mapping of DNase I hypersensitive sites in rare cell populations using single-cell DNase sequencing. Nat Protoc 12:2342-2354 |
| Stanton, Benjamin Z; Hodges, Courtney; Crabtree, Gerald R et al. (2017) A General Non-Radioactive ATPase Assay for Chromatin Remodeling Complexes. Curr Protoc Chem Biol 9:1-10 |
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