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Genomic methods for measuring DNA replication dynamics

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Abstract

Genomic DNA replicates according to a defined temporal program in which early-replicating loci are associated with open chromatin, higher gene density, and increased gene expression levels, while late-replicating loci tend to be heterochromatic and show higher rates of genomic instability. The ability to measure DNA replication dynamics at genome scale has proven crucial for understanding the mechanisms and cellular consequences of DNA replication timing. Several methods, such as quantification of nucleotide analog incorporation and DNA copy number analyses, can accurately reconstruct the genomic replication timing profiles of various species and cell types. More recent developments have expanded the DNA replication genomic toolkit to assays that directly measure the activity of replication origins, while single-cell replication timing assays are beginning to reveal a new level of replication timing regulation. The combination of these methods, applied on a genomic scale and in multiple biological systems, promises to resolve many open questions and lead to a holistic understanding of how eukaryotic cells replicate their genomes accurately and efficiently.

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Abbreviations

MFA:

Marker frequency analysis

ORC:

Origin recognition complex

MCM:

Mini-chromosome maintenance

ChIP:

Chromatin immunoprecipitation

ARS:

Autonomous replicating sequence

SNS-seq:

Short nascent strand sequencing

NSCR:

Nascent strand capture and release

HU:

Hydroxyurea

ini-seq:

Initiation site sequencing

TSS:

Transcription start sites

G4:

G-quadruplex

LCL:

Lymphoblastoid cell line

ESC:

Embryonic stem cell

FISH:

Fluorescence in situ hybridization

SMARD:

Single-molecule analysis of replicating DNA

WGA:

Whole-genome amplification

DOP-PCR:

Degenerate-oligonucleotide-primed PCR

MALBAC:

Multiple annealing and looping-based amplification cycles

LIANTI:

Linear amplification via transposon insertion

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Funding

Work in the Koren lab is supported by grants DP2GM123495 from the National Institutes of Health and MCB-1921341 from the National Science Foundation. MLH is supported by the National Science Foundation Graduate Research Fellowship DGE-1650441.

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    1. Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA

      Michelle L. Hulke, Dashiell J. Massey & Amnon Koren

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    1. Michelle L. Hulke
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    MLH, DJM, and AK wrote the paper.

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    Correspondence to Amnon Koren.

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    Michelle L. Hulke and Dashiell J. Massey contributed equally to this work.

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    Hulke, M.L., Massey, D.J. & Koren, A. Genomic methods for measuring DNA replication dynamics. Chromosome Res 28, 49–67 (2020). https://doi.org/10.1007/s10577-019-09624-y

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