Multiplexed single-molecule experiments reveal Cas9 nucleosome invasion dynamics

K Makasheva, L Bryan, M Jinek, B Fierz - Biophysical Journal, 2022 - cell.com
K Makasheva, L Bryan, M Jinek, B Fierz
Biophysical Journal, 2022cell.com
Yoonjin Kim1, Alexander Y. Afanasyev2, Igor S. Tolokh1, Igor V. Sharakhov3, Alexey V.
Onufriev4. 1Computer Science, Virginia Tech, Blacksubrg, VA, USA, 2Biomedical
Engineering and Mechanics, Virginia Tech, Blacksburg, VA, USA, 3Entomology, Virginia
Tech, Blacksburg, VA, USA, 4Computer Science and Physics, Virginia Tech, Blacksburg, VA,
USA. Multiple studies have shown a correlation between gene expression and positioning of
the genes at nuclear lamina which lines nuclear envelope (NE). However, the exact …
Yoonjin Kim1, Alexander Y. Afanasyev2, Igor S. Tolokh1, Igor V. Sharakhov3, Alexey V. Onufriev4. 1Computer Science, Virginia Tech, Blacksubrg, VA, USA, 2Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA, USA, 3Entomology, Virginia Tech, Blacksburg, VA, USA, 4Computer Science and Physics, Virginia Tech, Blacksburg, VA, USA. Multiple studies have shown a correlation between gene expression and positioning of the genes at nuclear lamina which lines nuclear envelope (NE). However, the exact relationship between proximity to NE and reduced gene expression is still unclear. Here, we ask whether there is a causal connection between noticeable changes in gene expression level in Drosophila nuclei and frequency of localization at the NE of the groups of genes in topologically associating domains (TADs) of Drosophila nuclei. We use a recently developed coarse-grained model of Drosophila nuclei at TAD resolution, which takes into account different epigenetic classes of TADs, and experimentally observed linear distribution of lamina associated domains (LADs), with available genome-wide transcription profiles in the wild type (WT) and lamin depleted (LD) nuclei. We introduce a new, TAD normalized, metric for transcription reads, Read Per Kilobase Million per TAD (RPKMT), which shows consistency with epigenetic TAD types and better describes chromatin activity levels at TAD resolution. The model properly reproduces different experimentally observed average TAD positioning at the NE for both WT and LD nuclei (chromatin density profiles) and can predict the probabilities of individual TADs to be in the layer adjacent to the NE. We compare model frequencies of physical TAD location at the NE in WT and LD nuclei with transcription level. We have analyzed gene expressions in TADs in several ways, including element-wise Pearson’s score, TAD binning based on the NE contact frequencies in WT nuclei, distribution of epigenetic classes of TADs in each bin, and along with TADs containing LADs. The results of our genomics analysis suggest that proximity of chromatin to the nuclear envelope does not, by itself, affect gene expression in Drosophila.
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