Reactivation of developmentally silenced globin genes through forced linear recruitment of remote enhancers

The human genome contains regulatory DNA elements, known as enhancers, that can activate gene transcription over long chromosomal distances. Here, we showed that enhancer distance can be critical for gene silencing. We demonstrated that linear recruitment of the normally distal strong HBB enhancer to developmentally silenced embryonic HBE or fetal HBG promoters through deletion or inversion of intervening DNA sequences led to strongly reactivated expression in adult erythroid cells and ex vivo differentiated hematopoietic stem and progenitor cells. A similar observation was made for the HBA locus in which deletion-to-recruit of the distal enhancer strongly reactivated embryonic HBZ expression. Overall, our work assigned function to seemingly nonregulatory genomic segments; by providing linear separation, they may support genes to autonomously control their transcriptional response to distal enhancers.

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Publication Details

Journal
Blood
Published
2025-06-02
DOI
https://doi.org/10.1182/blood.2024028128
Citations
3
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
2.42
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article

Reactivation of developmentally silenced globin genes through forced linear recruitment of remote enhancers

Wouter de Laat, Peter H.L. Krijger, Marjon J.A.M. Verstegen, Jeffrey van Haren et al.
3 citations
Blood
Genomics and Chromatin Dynamics
2.42
article

Reactivation of developmentally silenced globin genes through forced linear recruitment of remote enhancers

Wouter de Laat, Peter H.L. Krijger, Marjon J.A.M. Verstegen, Jeffrey van Haren, Thijs C. J. Verheul, Anna-Karina Felder, Han Verhagen, Emile van den Akker, Sjoerd J. D. Tjalsma, Sjaak Philipsen, Rezin Majied, Rebecca Mohnani, Richard Gremmen
article en
3 citations

Abstract

The human genome contains regulatory DNA elements, known as enhancers, that can activate gene transcription over long chromosomal distances. Here, we showed that enhancer distance can be critical for gene silencing. We demonstrated that linear recruitment of the normally distal strong HBB enhancer to developmentally silenced embryonic HBE or fetal HBG promoters through deletion or inversion of intervening DNA sequences led to strongly reactivated expression in adult erythroid cells and ex vivo differentiated hematopoietic stem and progenitor cells. A similar observation was made for the HBA locus in which deletion-to-recruit of the distal enhancer strongly reactivated embryonic HBZ expression. Overall, our work assigned function to seemingly nonregulatory genomic segments; by providing linear separation, they may support genes to autonomously control their transcriptional response to distal enhancers.

BloodVol. 146(6)
Royal Netherlands Academy of Arts and Sciences (NL), Utrecht University (NL), University Medical Center Utrecht (NL), Sanquin (NL), Hubrecht Institute for Developmental Biology and Stem Cell Research (NL), Erasmus University Rotterdam (NL)
Openalex Percentile: Top 11%
Genomics and Chromatin Dynamics
2.42
DOIOpen Access PDFOpenAlex
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