Genome accessibility is widely preserved and locally modulated during mitosis.
Mitosis entails global alterations to chromosome structure and nuclear architecture, concomitant with transient silencing of transcription. How cells transmit transcriptional states through mitosis remains incompletely understood. While many nuclear factors dissociate from mitotic chromosomes, the observation that certain nuclear factors and chromatin features remain associated with individual loci during mitosis originated the hypothesis that such mitotically retained molecular signatures could provide transcriptional memory through mitosis. To understand the role of chromatin structure in mitotic memory, we performed the first genome-wide comparison of DNase I sensitivity of chromatin in mitosis and interphase, using a murine erythroblast model. Despite chromosome condensation during mitosis visible by microscopy, the landscape of chromatin accessibility at the macromolecular level is largely unaltered. However, mitotic chromatin accessibility is locally dynamic, with individual loci maintaining none, some, or all of their interphase accessibility. Mitotic reduction in accessibility occurs primarily within narrow, highly DNase hypersensitive sites that frequently coincide with transcription factor binding sites, whereas broader domains of moderate accessibility tend to be more stable. In mitosis, proximal promoters generally maintain their accessibility more strongly, whereas distal regulatory elements tend to lose accessibility. Large domains of DNA hypomethylation mark a subset of promoters that retain accessibility during mitosis and across many cell types in interphase. Erythroid transcription factor GATA1 exerts site-specific changes in interphase accessibility that are most pronounced at distal regulatory elements, but has little influence on mitotic accessibility. We conclude that features of open chromatin are remarkably stable through mitosis, but are modulated at the level of individual genes and regulatory elements.
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
Chris C-S
CC
Hsiung
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
Christapher S
CS
Morrissey
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
Maheshi
M
Udugama
Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina 27708, USA;
Christopher L
CL
Frank
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
Cheryl A
CA
Keller
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
Songjoon
S
Baek
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
Belinda
B
Giardine
Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA; Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina 27708, USA.
Gregory E
GE
Crawford
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
Myong-Hee
MH
Sung
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
Ross C
RC
Hardison
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; blobel@email.chop.edu.
Gerd A
GA
Blobel
D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D002875:Chromosomes; D019295:Computational Biology; D019175:DNA Methylation; D003850:Deoxyribonuclease I / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000378:metabolism; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D007399:Interphase / Q000235:genetics; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D050982:GATA1 Transcription Factor; D014157:Transcription Factors; D003850:Deoxyribonuclease I