Linking the dynamics of chromatin occupancy and transcription with predictive models

Tran, Trung Q.; MacAlpine, Heather K.; Tripuraneni, Vinay; Mitra, Sneha; MacAlpine, David M.; Hartemink, Alexander J.

doi:10.1101/gr.267237.120

Cited by 9 publications

(12 citation statements)

References 77 publications

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“…As shown for select time points representing late G1 (α-factor), early S (20 min), and M (60 min) phases, we observed fluctuations in the dyad positions of the ACS-proximal nucleosomes and in the occupancy of ACS-bound small fragments ( Figure 1 B,C). A score for nucleosome occupancy and position was calculated using a two-dimensional nucleosome kernel modeled on the MNase fragments associated with nucleosomes mapped by an orthogonal chemical cleavage method [ 32 , 33 ] ( Supplementary Figure S3 ). A score for small factor occupancy (e.g., ORC, pre-RC, and pre-IC) at origins was generated by calculating the density of small protected fragments less than 120 bp at each origin of DNA replication.…”

Section: Resultsmentioning

confidence: 99%

“…The progression of the replication fork results in eviction of histones and disruption of nucleosome positioning [ 19 ]. We utilized Shannon entropy to assess the level of nucleosome organization [ 33 ] throughout the cell cycle. Well-positioned nucleosomes have a low entropy while disorganized nucleosomes exhibit a high entropy.…”

Section: Resultsmentioning

confidence: 99%

“…This matrix represents the approximate size and coverage distribution of MNase-seq reads centered at a canonical well-positioned nucleosome. A two-dimensional kernel was then derived using a bivariate Gaussian distribution parameterized by the marginal means and variances of the matrix [ 33 ]. The variance of fragment size dimension ( y -axis) was set to 1/16 of the original marginal variance and the variance of midpoint position dimension ( x -axis) was set to 1/4 of the original marginal variance.…”

Section: Methodsmentioning

confidence: 99%

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Cell-Cycle–Dependent Chromatin Dynamics at Replication Origins

Hartemink

MacAlpine

2021

Genes

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Origins of DNA replication are specified by the ordered recruitment of replication factors in a cell-cycle—dependent manner. The assembly of the pre-replicative complex in G1 and the pre-initiation complex prior to activation in S phase are well characterized; however, the interplay between the assembly of these complexes and the local chromatin environment is less well understood. To investigate the dynamic changes in chromatin organization at and surrounding replication origins, we used micrococcal nuclease (MNase) to generate genome-wide chromatin occupancy profiles of nucleosomes, transcription factors, and replication proteins through consecutive cell cycles in Saccharomyces cerevisiae. During each G1 phase of two consecutive cell cycles, we observed the downstream repositioning of the origin-proximal +1 nucleosome and an increase in protected DNA fragments spanning the ARS consensus sequence (ACS) indicative of pre-RC assembly. We also found that the strongest correlation between chromatin occupancy at the ACS and origin efficiency occurred in early S phase, consistent with the rate-limiting formation of the Cdc45–Mcm2-7–GINS (CMG) complex being a determinant of origin activity. Finally, we observed nucleosome disruption and disorganization emanating from replication origins and traveling with the elongating replication forks across the genome in S phase, likely reflecting the disassembly and assembly of chromatin ahead of and behind the replication fork, respectively. These results provide insights into cell-cycle–regulated chromatin dynamics and how they relate to the regulation of origin activity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cell-Cycle–Dependent Chromatin Dynamics at Replication Origins

Hartemink

MacAlpine

2021

Genes

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“…We generated RNA-seq and paired-end MNase-seq data from S. cerevisiae before and after cadmium treatment ( 19 ). These are available for download at the NCBI Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo ) under accession number GSE153609.…”

Section: Methodsmentioning

confidence: 99%

RoboCOP: jointly computing chromatin occupancy profiles for numerous factors from chromatin accessibility data

Mitra

Zhong

Tran

et al. 2021

Nucleic Acids Research

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Chromatin is a tightly packaged structure of DNA and protein within the nucleus of a cell. The arrangement of different protein complexes along the DNA modulates and is modulated by gene expression. Measuring the binding locations and occupancy levels of different transcription factors (TFs) and nucleosomes is therefore crucial to understanding gene regulation. Antibody-based methods for assaying chromatin occupancy are capable of identifying the binding sites of specific DNA binding factors, but only one factor at a time. In contrast, epigenomic accessibility data like MNase-seq, DNase-seq, and ATAC-seq provide insight into the chromatin landscape of all factors bound along the genome, but with little insight into the identities of those factors. Here, we present RoboCOP, a multivariate state space model that integrates chromatin accessibility data with nucleotide sequence to jointly compute genome-wide probabilistic scores of nucleosome and TF occupancy, for hundreds of different factors. We apply RoboCOP to MNase-seq and ATAC-seq data to elucidate the protein-binding landscape of nucleosomes and 150 TFs across the yeast genome, and show that our model makes better predictions than existing methods. We also compute a chromatin occupancy profile of the yeast genome under cadmium stress, revealing chromatin dynamics associated with transcriptional regulation.

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“…As shown for select time points representing late G1 (α-factor), early S (20 min) and M (60 min) phases, we observed fluctuations in the dyad positions of the ACS-proximal nucleosomes and the occupancy of ACS-bound small fragments (Figures 1B and 1C). A score for nucleosome occupancy and position was calculated using a two-dimensional nucleosome kernel modeled on the MNase fragments associated with nucleosomes mapped by an orthogonal chemical cleavage method [32,33](Figure S3). A score for small factor occupancy (e.g.…”

Section: Chromatin Occupancy Profiling Of Replication Origins Throughout the Cell Cyclementioning

confidence: 99%

Cell cycle-dependent chromatin dynamics at replication origins

Li¹,

Hartemink²,

MacAlpine

2021

Preprint

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Origins of DNA replication are specified by the ordered recruitment of replication factors in a cell cycle dependent manner. The assembly of the pre-replicative complex in G1 and the pre-initiation complex prior to activation in S-phase are well characterized; however, the interplay between the assembly of these complexes and the local chromatin environment is less well understood. To investigate the dynamic changes in chromatin organization at and surrounding replication origins, we used micrococcal nuclease (MNase) to generate genome-wide chromatin occupancy profiles of nucleosomes, transcription factors and replication proteins through consecutive cell cycles in Saccharomyces cerevisiae. During each G1 phase of two consecutive cell cycles, we observed the downstream repositioning of the origin-proximal +1 nucleosome and an increase in protected DNA fragments spanning the ARS consensus sequence (ACS) indicative of pre-RC assembly. We also found that the strongest correlation between the chromatin occupancy at the ACS and origin efficiency occurred in early S-phase consistent with the rate limiting formation of the Cdc45-Mcm2-7-GINS (CMG) complex being a determinant of origin activity. Finally, we observed nucleosome disruption and disorganization emanating from replication origins and traveling with the elongating replication forks across the genome in S-phase, likely reflecting the disassembly and assembly of chromatin ahead of and behind the replication fork, respectively. These results provide insights into cell cycle-regulated chromatin dynamics and how they relate to the regulation of origin activity.

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Linking the dynamics of chromatin occupancy and transcription with predictive models

Cited by 9 publications

References 77 publications

Cell-Cycle–Dependent Chromatin Dynamics at Replication Origins

Cell-Cycle–Dependent Chromatin Dynamics at Replication Origins

RoboCOP: jointly computing chromatin occupancy profiles for numerous factors from chromatin accessibility data

Cell cycle-dependent chromatin dynamics at replication origins

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