Instruction of epigenetic states from dna sequences

Access through your institution Buy or subscribe Understanding how the same DNA sequence instructs an abundance of transcriptional programmes associated with different cell states cannot be

complete without considering epigenetics. The ability of cells to commit and memorize specific epigenetic programmes is essential for the construction of complex tissues and organs during

development. However, because transcriptional and epigenetic changes go hand in hand, determining the roles of epigenetic mechanisms in cell state acquisition remains a notoriously difficult

task. During my undergraduate studies, I stumbled upon a landmark paper from the lab of Howard Cedar, which sparked my long-term interest in this problem. This study aimed to address how

genome-wide DNA methylation patterns are established and instructed by the DNA sequence. In vertebrates, 5-methylcytosine occurs mainly in the context of CG dinucleotides, and somatic cells

present a bimodal landscape of methylation: the bulk of the genome comprises low-density CG sequences and is uniformly decorated by methylation, whereas high-density CG regions, termed CG

islands (CGIs), are largely hypomethylated. The coupling of methylation maintenance to DNA replication provides a simple and robust mechanism for epigenetic memory across cell divisions.

Yet, an unresolved question was how the bimodal methylation landscape is initially installed in the early embryo. Utilizing the ability of mouse embryonic stem cells to methylate and

demethylate exogenously introduced genomic sequences, the authors showed that an isolated 5′ region of the _Aprt_ gene contains all the necessary information to be recognized as an

endogenous CGI. When introduced unmethylated to the cells, the sequence remained hypomethylated. But when the same sequence was introduced fully methylated, it underwent substantial 

demethylation. A major finding of this study was the identification of sequence motifs that recruit the Sp1 transcription factor to the _Aprt_ CGI. In turn, the binding of Sp1 was shown to

protect the CGI from acquiring de novo methylation in stem cells and embryos. This principle proved to be a general mechanism by which trans-acting factors establish the stereotypic

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ARTICLE * Brandeis, M. et al. Sp1 elements protect a CpG island from de novo methylation. _Nature_ 371, 435–438 (1994) Article  CAS  PubMed  Google Scholar  Download references AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Yonatan Stelzer Authors * Yonatan Stelzer View author publications

You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Yonatan Stelzer. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE

THIS ARTICLE Stelzer, Y. Instruction of epigenetic states from DNA sequences. _Nat Rev Mol Cell Biol_ 24, 164 (2023). https://doi.org/10.1038/s41580-023-00577-z Download citation *

Published: 16 January 2023 * Issue Date: March 2023 * DOI: https://doi.org/10.1038/s41580-023-00577-z SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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