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A changing paradigm of transcriptional memory propagation through mitosis

Abstract

The highly reproducible inheritance of chromosomes during mitosis in mammalian cells involves nuclear envelope breakdown, increased chromatin compaction, loss of long-range intrachromosomal interactions, loss of enhancer–promoter proximity, displacement of many transcription regulators from the chromatin and a marked decrease in RNA synthesis. Despite these dramatic changes in the mother cell, daughter cells are able to faithfully re-establish the parental chromatin and gene expression features characteristic of the cell type. Pioneering studies of mitotic chromatin signatures showed that despite global repression of transcription, the Hsp70 gene promoter retains an open chromatin conformation, which was proposed to allow the reactivation of the Hsp70 gene upon completion of mitosis — a phenomenon termed mitotic bookmarking. It was later shown that various cell-type-specific transcription factors, such as GATA-binding factor 1 (GATA1) in erythroblasts and forkhead box protein A1 (FOXA1) in hepatocytes, remain bound at a subset of their interphase binding sites in mitosis. Such bookmarking transcription factors remain on chromosomes in mitosis and have been shown to enable a subset of genes to be reactivated in a timely fashion upon mitotic exit. In addition, sensitive new methods to measure transcription revealed that mitotic cells retain residual transcription at a large number of genes. Furthermore, genes recover their interphase level of transcription in distinct waves. Thus, gene expression is precisely regulated as cells pass through mitosis to ensure faithful propagation of cell identity and function through cellular generations.

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Acknowledgements

The authors thank P. Navarro (Institut Pasteur) for comments on the manuscript and M. Song for help in its preparation. Research on mitotic transcription has been supported by US National Institutes of Health (NIH) grant T32GM00812 to K.C.P., by Fondation pour la Recherche Médicale grant 40334 to J.L. and by NIH grant GM36477 to K.S.Z.

Reviewer information

Nature Reviews Molecular Cell Biology thanks D. Suter, P. Navarro and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

The authors contributed equally to all aspects of the article.

Competing interests

The authors declare no competing interests.

Correspondence to Kenneth S. Zaret.

Glossary

Epigenetic control of gene expression

Mechanisms independent of DNA alterations through which the gene expression programme particular to a cell type is recapitulated in daughter cells after cell division.

Footprinting

A method of detecting where proteins are bound to DNA on the basis of their accessibility to enzymes such as DNase I or chemicals such as DMS or potassium permanganate.

General transcription factors

Proteins that act at promoters to enable transcription of many classes of genes.

Promoter transcription factors

General transcription factors that localize to promoters.

Architectural transcription factors

Transcription factors, such as CTCF (CCCTC-binding factor), that bring regions of the genome together to form higher-order chromatin structures, which have important roles in gene expression regulation.

HALO-tag

A modified enzyme that binds to a synthetic ligand target and can be fused to a protein of interest for visualization.

Pioneer factor

Transcription factor that can directly bind nucleosomal DNA in chromatin.

Topologically associated domains

(TADs). Boundary-insulated chromosomal segments within which sequences preferentially contact each other.

Housekeeping genes

Genes that are responsible for the general functions of a cell, such as growth and metabolism, independent of the cell’s specialized function.

Click reaction

The copper-catalysed conjugation of an azide with an alkyne to yield a five-part heteroatom ring.

Interphase contamination

Transcriptional signal in a population of mitotic cells that results from contaminating interphase cells in that population. Importantly, for studies of mitotic transcription, the high transcriptional activity of the contaminating interphase cells, relative to the low level that occurs in mitotic cells, can lead to overestimation of transcription during mitosis.

Spike-in controls

Short, known sequences of DNA or RNA that are added to a sample at a known quantity at the beginning of a high-throughput sequencing assay to help normalize for synthesis and recovery when comparing different samples.

DNase I hypersensitivity

The ability of a segment of DNA in chromatin to be digested by DNase I owing to the accessibility of this segment (lack of local compaction).

Assay for transposase-accessible chromatin with sequencing

(ATAC–seq). A method that uses the Tn5 transposase to probe the genome for accessibility.

Amphiphilic protein

A protein that is hydrophobic on one end and hydrophilic on the other end.

Histone variant

A substitute for one of the canonical histones in a nucleosome.

Nocodazole

A compound that prevents microtubule polymerization, thereby blocking the formation of the metaphase plate.

Enhancer RNAs

(eRNAs). RNAs that are generated from the site of enhancer sequences, presumably as a by-product of Pol II activity.

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Further reading

Fig. 1: Mitotic bookmarking by transcription factors.
Fig. 2: Histone modifications in mitosis.
Fig. 3: Mitotic cells maintain low levels of transcription.
Fig. 4: Transcription reactivation during mitotic exit.